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Geological timescales

• Miocene Epoch: 23 million - 5.3 million years ago
• Pliocene Epoch: 5.3 million - 2.5 million years ago
• Pleistocene Epoch (Ice Age): 2.5 million - 12,000 years ago
• Holocene Epoch: 12,000 years ago – present
• Anthropocene Epoch: when human activities started to have a significant global impact on Earth’s geology and ecosystems


Human (Homo) timescale

• Paleolithic age (stone age): 2.5 million years ago to 10,000 years ago
• Neolithic age (late stone age with emergence of plant and animal domestication): 10,000 - 4,000 years ago.
• Bronze age (metal tools widely used): 5,300 - 2,400 years ago
• Iron age: 3,300 - 1,600 years ago
• Silicon age: 1971 - present


earlist evidence of fire where? When? Who?

-eralist evidence of use of fire was 1 million yrs ago in South Africa by Homo erectus


First Evidence, era, who, when?

-2.5 mil yrs ago (Paleolithic)
-Homo habilis


Evolutionary sequence & brain size

• 7-8 MYA: hominin/hominid lineage split from chimpanzee lineage.
• Pan troglodytes (chimpanzee) brain size today 300-400 cm3. • Pan paniscus (bonobo) brain size today 300-400 cm3 . • 7 MYA: Sahelanthropus tchadensis brain size 320-380 cm3. • 4.4 MYA: Ardipithecus ramidus brain size 300-330 cm3. • 3.2 MYA: Australopithecus afarenesis brain size 400-500
cm3. • 2.5 MYA: Homo habilis brain size 600 cm3. • 1.8 MYA – 200,000 YA: Homo erectus brain size 680-1100
cm3 and its offshoot clades in Africa and Europe.
• 400,000 – 28,000 YA: Homo neanderthalensis brain size similar to Homo sapiens.
• 200,000 YA - present: Homo sapiens brain size 1350 cm3.


Homo erectus tool making

-1.5 mil yrs ago
-rounded tools
-1.5 and 250,000 ago tools did not change much


Symolic art

-First evidence was 75,000 years ago- South Africa


Upper (Late) Paleolithic revolution

-40,000 years ago in Europe expansion in tool making ... known as



-Two factors which likely initiated use of clothing in humans are... 1) Loss of much of the body hair and 2.) exposure to cooler temperatures through climate change and migration
-bone needles used to make clothes date back to 40,000 yrs.
-Molecular clock DNA sequences from head and body lice suggests a divergence date of around 100,000 years ago which suggests that use of clothing may have started around this time.
-African hair shafts are more elliptical in shape than European hair shafts and this makes it more difficult for head lice to attach eggs to African hair shafts.



- Homo language is estimated to have first developed from 160,000 -80,000 years ago
-Broca's and Wernicke's areas of the cerebral cortex & change in shape of larynx helped Hominins them speak


Genetic abnormalities which
impair language

-Dyslexia is neurobehavioral disorder where individual with normal intelligence experiences difficulty with reading, writing, and spelling
-Mutations in ‘reading disorder’ genes include DCDC2 on chromosome 6 and ROBO1 on chromosome 3 together represent 20% of cases of dyslexia.



-language problem
-a transcription factor that consists of 715 amino acids (differs from mice by 3 amino acids & gorillas, chimps by 2 amino acids)
-the high rate of divergence after the chimp/human divergenceis suggestive of the role of FOXP2 in language development


Culture and Society

-pre-agriculutral human groups often comprised from 50-150
-two very important cultural innovations were ag & human settlements/villages


Homo origins and migrations

• The origin and migration of modern humans can be documented with reasonable certainty with archeological, linguistic, & molecular genetic analysis.
• Major dispersals of Homo species.
• Homo habilis did not migrate out of Africa.
• Homo erectus spread out of Africa into Georgia 1.8 million
years ago, Java/Indonesia 1.7 million years ago, and into East Asia 1.4 million years ago.
• A hominin footprint dated 0.8-1.0 million years old was found in Happisburgh, UK (Plos One, Feb 2014, 9(2): e88239)
• Homo neanderthalensis is a descendent of Homo erectus offshoot Homo heidelbergensis.
• Homo neanderthalensis populated Europe from 400,000 -28,000 years ago.


Homo sapiens origins and migration

• Genetic and fossil evidence confirms a sub-Saharan origin for anatomically modern humans (Box 6.8).
• Homo sapiens evolved from Homo erectus
offshoot Homo rhodesiensis in Africa 200,000 years ago.
• Homo sapiens first left Africa and migrated into Middle East (Israel/Palestine) 100,000-120,000 years ago.
• Homo sapiens remained restricted to Africa and the Middle East until about 60,000 - 70,000 years ago, when a relatively small group of humans departed from eastern Africa across the mouth of the Red Sea and migrated into Asia and Europe.
• This small group became the founder population for all humans living outside of Africa.
• By 35,000 years ago Homo sapiens had dispersed throughout Africa, Asia, and into Europe.
-The westward migration of Homo sapiens
into Europe 40 - 50,000 years ago
• By 15,000 years ago Homo sapiens had dispersed into North and South America.
• There was a southward, westward, and eastward migration of Taiwanese Austronesian culture began around 5,500 years ago.


Methods for mapping human genetic diversity

• Genetic markers (maternal mitochondrial DNA and certain Y-chromosome DNA) are inherited only from a single parent and are not subject to recombination during gametogenesis.
• Consequently, DNA sequence patterns (haplotypes) in these type of DNA are passed unchanged to the offspring
• It is possible to recreate the history of human migration by tracking genetic markers in mitochondrial DNA (for the female lineage or matriline) and Y-chromosome DNA (for the male lineage or patriline) among different populations


Hominin origins and mitochondrial DNA

• Genetic and fossil evidence points to a sub-Saharan origin for anatomically modern humans (Box 6.8).
• The genetic lineages found in the Khosian (Kung san) people of southwestern Africa provide evidence that they are among some of the oldest extant human populations.
• Human mitochondrial DNA lineages coalesce about 140,000 years ago, or in other words they can be traced to a single woman who lived at that time (mitochondrial Eve).


Hominin origins and Y chromosome variation

• Studies of the Y chromosome variation point to a somewhat later coalescence than mitochondrial DNA
• This apparent difference may be the result of a smaller effective population size in males possibly arising from the socio-cultural phenomenon where, in some traditional societies, a few dominant men father most of the children.


Out-of-Africa migration

• Based on analysis of mitchondrial DNA, it is estimated that 40-50 matrilineal lineages existed in Africa, at the time of the out-of-Africa event 60-70,000 years ago.
• Only two of the 40-50 matrilineal lines (L3M and L3N) contribute to worldwide non-African diversity due to this out-of-Africa migration generated founder effect.
• Similarly, all non-African Y chromosomes carry the mutation M168.


Out-of-Africa migration
and linguistic diversity

• Modern sub-Saharan African populations have indigenous languages which are the most diverse with more phonetic sounds.
• People in the regions last to be populated by modern humans (Western Europe, the Americas, and Oceania) have indigenous languages which are the least diverse with fewer phonetic sounds.
• The analysis of sounds used in 504 languages around the world found that languages tend to be less diverse, with fewer phonetic sounds, the farther their speakers are from southwestern Africa.
• The pattern implies that language may have originated once among early humans, then became less and less diverse the farther humans migrated from southwestern Africa.


Homo sapiens Asia migrations

• Some proceeded on across the steppes (semi-arid grasslands) of Central Asia to populate Siberia.
• Some traveled south of the Central Asia massif (mountains) along coastal areas to India, southeast Asia, Papua New Guinea, Australia, and China ( 48,000 years ago).
• There is evidence that when coastal migrants passed through SE Asia some traveled north through SE Asia up to what is now China
which may explain the genetic differentiation between north and south Han Chinese.


Hair morphology in
East Asians & Native Americans

Coarser hair texture in East Asians hair appears to be the result of a single amino acid change from a mutation that occurred 35,000 years ago that increases the effectiveness of a particular cell-surface receptor protein called EDAR.
• It it not clear that there is an adaptive benefit of course hair, however the receptor also has adaptive effects on teeth, sweat glands, and skin.
• The mutation probably occurred during human migration through Central Asia, since it occurs in high frequency in East Asians and Native Americans, but is virtually absent from Europeans and Africans.


Sexual selection of Y chromosome in Central Asia

• An example of an application of Y chromosome analysis is as follows.
• 8% of men now living in Central Asia carry a Y chromosome haplotype that can be traced back to a specific man who lived in Mongolia about 1000 years ago (‘Ghenghis Khan’s Y chromosome’) which is an example of sexual selection.


Human migration to Europe routes

• Route #1: from Central Asia via a route north of the Black Sea
• Route #2: via the Mediterranean route from the Levant.
• Homo sapiens encountered and co-existed and interbred with Homo neanderthalensis
who were in Europe until 28,000 years ago.


Evidence of Homo sapiens interbreeding with Homo neanderthalensis Europe

-present-day Homo sapiens from lineages outside of sub-saharan Africa indicates that on average 2.5% of the DNA is from Neanderthal
-Neanderthals shared genetic variants with present-day humans (Homo sapiens)
in Europe and Asia but not with present-day humans (Homo sapiens) in sub-Saharan Africa.
-This can be explained by the fact that Neanderthal range did not extend into Africa.



• Denisovans are proposed to represent a group that shares a common origin with Neanderthals
• May have been widespread in Asia and Europe during the Late Pleistocene epoch
• Disappeared around 30,000 years ago
A 40,000 year old finger of a girl and a tooth were found in Denisova cave in southern Siberia.
• Scientists at the Max Planck Institute for Evolutionary Anthropology sequenced the genome of this archaic hominin DNA
• 4-6% of present day Melanesian genomes is Denisovan
• 1% of present day SE and East Asian genome is Denisovan
• A 400,000 year old thigh bone from Spain has DNA that resembles Denisovan DNA


Human migration to the Americas

• At least 20,000 years ago the migration into the Americas occurred.
• One or more migrations by relatively small groups of Siberian humans over the landmass called Beringia which connected present day Siberia and Alaska between 20,000-8,000 years ago because of the fallen ocean level during the last glacial period.
• As the North American glaciers began to melt and recede about 20,000 years ago opened the way for southward migration and Homo sapiens
reached southern South America as early as 14,000 years ago.
• The original founding population was quite small.
• Given the low genetic diversity in Native people of the Americas, some investigators have proposed that the effective size of the migrating founder population was no larger than 70 individuals.
-An example of a migration induced genetic bottleneck which resulted in low genetic diversity in Native Americans is the fact that nearly all have blood type O (especially Mexico, Central and South American Indians), with a very low frequency of blood type A, and virtual absence of blood type B.


History of Pacific Island Settlement Austronesian arrivals via boats

- 950 BC: Western Polynesia (Samoa & Tonga)
- 700 AD: Eastern Polynesia (Moorea & Tahiti)
- 900-1,000 AD: Hawaii - 1,250 AD: New Zealand - 1,850 AD: Polynesians continued to
be seafarers up until this date


Variation from migration

• Some variation created by genetic bottlenecks may be influenced by drift and be non-adaptive.
• Some variation created by genetic bottlenecks may be influenced by selection and be adaptive.
• Gene pools in migrating populations change both for adaptive and non-adaptive reasons.


Human clines

• With many human characteristics/traits there is a continuous geographical gradient (cline) of a trait rather than discontinuous variation.


Thomson’s rule

-nose more narrow the colder the climate and drier
-allows nose to warm and humidify the air before it reaches the lungs


Allen’s rule

-humans in cold places are selected for shorter limbs relative to body trunk to reduce the surface area heat loss


Bergmann’s rule

-homeothermic species, subpopulations in colder climates have larger average mass per individual than populations in warmer climates.
-The larger average mass of these individuals has relatively less surface area in relation to volume which results in less heat



• Deoxyribonucleic acid is a nucleic acid that consists of two long chains of nucleotides twisted together into a double helix and joined by hydrogen bonds between complementary bases adenine and thymine or cytosine and guanine.


Complementary Bases

• Adenine and guanine are fused five-and six-membered heterocyclic compounds called purines.
• Cytosine and thymine are six-membered rings called pyrimidines.


DNA versus RNA

• A 5th pyrimidine base, called uracil (U), usually takes the place of thymine in RNA and differs from thymine by lacking a methyl group on its ring.
• The sugar in DNA is the pentose sugar 2-deoxyribose while in RNA it is the pentose sugar ribose.



-Ribonucleic acid that is essential to all forms of life
-Unlike DNA most are single stranded
-Similar to DNA it is made up of long chains of nucleotides
-Messenger RNA (mRNA) carries genetic information that directs the synthesis of proteins.


what is the backbone?
what is the sugar?

-backbone of the DNA is made of alternating phosphate & sugar
- The sugar in DNA is 2-deoxyribose, which is a pentose (five-carbon) sugar.
-The sugars are joined together by phosphate groups that form phosphodiester bonds between carbon atoms of adjacent sugar rings.


What position are stands?
Asymmetric ends of DNA strands are?
how is dna read (transcribed)
how is DNA double helix stablized?
how many feet contain DNA in human body?

-strands are *antiparallel*
-5' (five prime) and 3 prime... *5' end having a terminal phosphate group and terminal hydroxyl group*
-* hydrogen bonds between nucleotides and base-stacking interactions among the aromatic bases.*
-10 feet


how many do humans have?

• Structure in cell nucleus that is bearer of genes.
• Reproduces itself through each cell division.
• Humans typically have 46 chromosomes (23 pairs) with 44 autosomes (22 pairs) and 2 sex chromosomes (1 pair).


what is a genome

-entire complement of DNA sequences in a cell or organism



-set of genes possessed by an individual organism



• Observable physical or biochemical characteristics of an organism, as determined by genetic makeup, environmental influences, and the interaction of these


how can they be recognized?

-One of multiple forms of the same gene, presumably differing by a mutation of the DNA sequence.
• Alleles may be recognized by their phenotypic effects.


Example of co-dominance

AB blood type


Incomplete dominance
what is it?
when does it occur?
example of it?

-Incomplete dominance is a form of intermediate inheritance in which one allele for a specific trait is not completely dominant over the other allele.
-when the phenotype of the heterozygous genotype is distinct from the oftern intermediate to the phenotypes of the homozygous genotypes
-sickle cell is an example of this, where the heterozygous state has expression that is sufficient enough to provide protection against malaria


Heterozygote advantage

- In order to have a heterozygote advantage, the alleles must demonstrate incomplete dominance with expression of both alleles resulting in an intermediate phenotype.


Exons definition

- segments of DNA coding for amino acids
- segments of DNA positioned in between exons
-any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product (messenger RNA) of a gene
- the number & size of introns is highly variable even among genes


Promoter *BOLD* definition

the control region responsible for binding various transcription factors that switch expression of the gene on or off


Transcription, RNA processing, & translation

• *Transcription* is the process of creating a complementary RNA copy of a sequence of DNA.
• *Transcription* produces *primary RNA transcript.*
• After transcription, the segments of the resulting primary RNA transcript corresponding to the introns are removed by splicing to leave a *messenger RNA* that binds to ribosomes and codes for the *protein*.
• In *translation,* messenger RNA (mRNA) produced by transcription is decoded by the ribosome to produce a protein.


Protein Production

DNA >* transcription* > Primary RNA transcript > *RNA processing (splicing)* > messenger RNA> *translation* > protein


Human Genome

- human haploid genome are contained in germ cells (eggs and sperm) consist of three billion DNA base pairs, while diploid genomes (found in somatic cells) have twice the DNA content
-Each human somatic cells contains two copies of the entire human genome
-human diploid genome contains about 6.3 billion base pairs in men and 6.4 billion in women
-difference in males and females is because of the different sizes of the Y and X chromosomes


Genetic variation in humans

-humans are 99.5% similar
-the .5% difference corresponds to on average about the one nucleotide difference every few hundred base pairs of DNA


Structural Variation in the
Human Genome

-lots of variation, more than what was thought there was
-much of structural variation in gene sequences does NOT appear to influence human health or disease, while in other cases it does
-can increase, reduce, the chances of getting a disease


Junk DNA

-thought to be junk before
-now researchers think the Junk DNA contain a large number of tiny genetic switches controlling how genes function within the cell


Sources of heritable genetic variation BOLD

-*Recombination* (in sexually reproducing organisms)
-* Epigenetic modification influences development and/or phenotypical plasticity:* environmental factors during the development of an individual that modify the phenotype through epigenetic modifications; there is some evidence that some of these epigenetic modifications can be passed on to a limited number of generations.


Causes of mutation

• Errors in DNA replication during mitosis or meiosis
• Physical damage to DNA by chemical mutagens, ionizing radiation, and other environmental factors


New mutations are heterozygous

-New mutation only affects one copy of DNA and individuals carrying a new mutation will be heterozygous for that mutation
-mutation may generate an allele that is dominant, co-dominant, recessive, or have incomplete dominance


Types of sequence variation that together account for
the 0.5% sequence diversity among individuals

• *SNPs* = single nucleotide polymorphisms.
*• Indel = insertion or deletion* of one or more nucleotides.
• *VNTRs = variable number of tandem repeats:* changes in the number of repeat sequences arranged in tandem (next to each other) arrays.
• *Structural polymorphism* caused by *CNVs (copy number variants)* and *segmental duplications.*
• *Inversion, duplication, or deletion* of whole genes or gene-sized blocks of non-coded DNA.
• *Chromosomal inversion.*
• *Aneuploidy,* which is duplication or deletion of whole chromosomes, can NOT be passed on to next generation.
• *Transposable elements.*


SNPs single nucleotide polymorphisms

• Single-base substitution of one nucleotide for another at a particular site in DNA.
• Human genome contains one SNP every few hundred nucleotides.
• Current estimates suggest about 10-12 million common SNPs in human population.


Genetic Evidence for Convergent Evolution of Light Skin in Europeans and East Asians through different SNP mutations

• The SNP (single nucleotide polymorphism) genetic mutations leading to light skin, are different among East Asians and Europeans.
• The two groups likely experienced a similar selective pressure due to settlement in northern latitudes.


SNP coding and non-coding

-occur in protein coding and non-coding sequences
-SNPs in coding sequences are more likely to have phenotypic effects which will be exposed to selection


Stop codon

-the nucleotide sequence of DNA or mRNA that specifies a particular amino acid
-three nucleotide sequence of DNA or mRNA that specifies a termination



- A= adenine
- T= thymine
- G= guanine
- C=cytosine
Base pairs:
-Guanine forms a base pair with cytosine
-Adenine forms a base pair with thymine (in RNA, thymine is replaced with uracil)


SNPs in coding regions
-Synonymous polymorphisms
-Non-synonymous polymorphisms

• *Synonymous polymorphisms* do not alter the amino acid sequence of the protein product and are silent.
• *Non-synonymous polymorphisms* affect the integrity of the protein product by two mechanisms: 1) alter amino acid sequence; 2) a stop codon is introduced which causes premature termination of the protein sequence.


1st cause of SNPs BOLD

• 1st cause: *mistakes in copying the DNA sequence during replication.*
• DNA polymerase copies DNA very accurately, however, there is an error rate of 10-10 to 10-11 per nucleotide, each replication of the diploid genome requires copying of 6 X 109 nucleotides, suggesting that an error will occur every few replications.


2nd cause of SNPs BOLD

• 2nd cause: chemical or physical mutagenesis caused by environmental chemical or ionizing radiation.
• While complex genetic mechanisms have evolved to detect and repair genetic damage caused by chemical and physical mutagens, these mechanisms are also not entirely free from error.


Indels BOLD

-*short insertions or deletions* usually of 1-3 base pairs, within the DNA sequence
-Rates of mutation that lead to indels are about 10 times lowers than those given rise to SNPs
- If *indel is three or a multiple of three bases long* they have potential to *cause insertion or deletion* of one or more amino acids.
• If length of *indel is not a multiple of 3 bases* it can cause a *frameshift mutation*.


Indel induced frameshift mutation

• A frameshift mutation can cause the reading of the codons to code for different amino acids.
• The earlier in the sequence the deletion or insertion occurs, the more altered the protein product.
• Single base insertion or deletion in Tay-Sachs


VNTRS=Variable Number of Tandem Repeats
how often to the repeat

• Segments of the genome where short- to medium-length blocks of nucleotide sequence are repeated in tandem arrays (next to each another).
• Typically, the length of the repeat unit of *microsatellites* is 1-6 base pairs and 10-30 repeats.
• However, it is possible to have the repeating unit of *minisatellites* up to 100 base pairs with up to 1000 repeats
- most VNTRs are neutral with little to no phenotypic effect, but some microsatellites can have effets
-exp: VNTR is the rapid expansion of the CAG trinucleotide microsatellite within the coding region of the Huntingtin gene which causes Huntington chorea/disease.


Structural polymorphisms: BOLD

-copy number variants & segmental duplications
• Abnormal number of copies of a section of DNA on a chromosome.
• Each variation may range from about one kilobase (1,000 nucleotide bases) to several megabases (1,000,000 nucleotide bases) in size.
-affected blocks are large enough to contain whole genes and the phenotypic effects of such events are related to changed in gene dosage
-such variation in gene dosafe is likely to be associated with disease states, inter-individual differences in drug metabolism, and nutritional history


Copy number variants

• Duplication or multiplication of a gene for the drug-metabolizing enzyme cytochrome P450 CYP2D6 (up to 13 copies of the gene have been reported in some people) leads to the ultrarapid metabolizer phenotype.
• People with this phenotype have extra copies of the gene and as a result metabolize some drugs more quickly.


People with this ultrarapid metabolizer phenotype treated with standard doses of drugs metabolized by P450 CYP2D6, may experience:

• *treatment failure* (e.g., with certain antipsychotics and antidepressants) because the drug is rapidly *metabolized and broken down.*
• *toxicity* with other drugs such as the analgesic codeine which is *rapidly metabolized and converted to its active metabolite,* morphine by this enzyme leading to an overdose.


Structural polymorphism:
*segmental duplication*

• *Segmental duplications* are segments of DNA with near-identical sequence.
• Approximately 4-5% of the human genome consists of duplicated sequence in large blocks (1,000s -100,000s of base pairs) which may be found on the same chromosome or on different chromosomes.


Chromosomal inversion
When does it occur
Most common inversion happens were

• A chromosome rearrangement in which a segment of a chromosome is reversed end to end.
• Occurs when a single chromosome undergoes breakage and rearrangement within itself.
• The most common inversion seen in humans is on chromosome 9; often has no effects, but may increase miscarriage and infertility in some people



-duplication or deletion of a whole chromosome.
-Trisomy 21 (Down’s Syndrome) has an extra chromosome for total of 47 chromosomes.
• Monosomy X (Turner’s Syndrome) has only one sex chromosome for a total of 45 chromosomes.


Transposable elements

• Retrotransposons are dispersed but repetitive DNA elements that can move within the genome by a ‘copy and paste’ mechanism, which inserts a new copy of the element at a new site.


Source of variations



Two processes in meiosis which shuffle genes

• 1st is recombination during which homologous chromosomes align and exchange segments of DNA sequence, thereby creating new allele combinations on each chromosome.
• 2nd is independent assortment/segregation
of chromosomes into haploid gametes.


Germ line mutations

• Germ line = the cell lineage (oogonia and spermatogonia) giving rise to gametes.
• Mutations are only relevant to evolutionary change when they occur in the germ line.
• Somatic mutation of somatic cells in other parts of the body can cause disease (such as colon cancer) in that individual, but are not transmitted to offspring.


Regions of genome that undergo no recombination

• Most of Y chromosome in males (used as studies as a marker of male ancestry)
• Mitochondrial DNA in females (not involved in meiosis and does not recombine...marker of ancestry)


Haplotype blocks

• Haplotype is a specific group of alleles located adjacent to one another on a DNA strand of a chromosome and tend to be inherited together.
• Genome is organized into haplotype blocks of about 10,000-20,000 base pairs that are transmitted more or less intact between generations.
• Haplotype blocks are separated by preferred sites (hotspots) of recombination.
• Haplotype-based methods offer a powerful approach to disease gene mapping, based on the association between causal mutations and the ancestral haplotypes on which they arose.
• Knowledge of haplotype structure and linkage disequilibrium is essential in mapping the genetic loci associated with disease causation and the study of population history.


Linkage, linkage map

• *Linkage*: certain gene loci and alleles stay together during meiosis and are inherited together.
• *Linkage map*: genetic map that shows the position of its known genes or genetic markers relative to each other in terms of recombination frequency.


Linkage disequilibrium BOLD

*Linkage disequilibrium*: occurrence of some combinations of alleles or genetic markers in a population more often or less often than would be expected from a random formation of haplotypes from alleles based on their frequencies.
-non random
• Alleles at loci which are physically closer together on the DNA strand are less likely to be separated during recombination (and thus be co-inherited) then are those which are further apart.
• Such alleles are said to possess linkage disequilibrium.


Linkage disequilibrium
is influenced by: BOLD

• 1)* Presence or absence of recombination hotspots between the
two loci.*
• 2) *The evolutionary time since the alleles at the two loci first evolved*
since even for closely spaced loci, linkage disequilibrium inevitably diminishes over time as recombination events separate them.


Haplotype structure, linkage disequilibrium & mapping of genetic loci

• The extent of linkage disequilibrium between known marker alleles and an unknown disease-causing allele provides information about the location of the disease allele.


Use of linkage disequilibrium to detect and assess adaptive evolution in humans
How it happens
recent adaptive evolution

• The basic principle of detecting adaptive evolution is the identification of increased linkage disequilibrium in the genomic region surrounding a locus that has undergone a selective sweep.
-genes invovled with skin pigmentation, brain development, muscle biochemistry, energy metabolism and immune system


What are two broad approaches to finding genes associated with inherited diseases

1. Linkage mapping
2. Association studies


Linkage mapping
-when is most effective and less effective

-Attempts to find correlations between patterns of disease occurrence in families and patterns of transmission in genetic markers e.g., known genes with obvious phenotypic effects, or particular gene sequences.
-if disease susceptibility is transmitted in the same pattern as the marker, then the disease causing gene appears to be physically close to the marker since they are not separated by recombination.
-most effective in highly penetrant monogenic disorders and is less effective in complex multifactorial mutli-loci disorders


Association studies

• Analyzes unrelated people with and without a disease (cases and controls) for the presence of particular alleles.
• If an allele is found more often in cases than in controls, then it (or a closely linked allele) is assumed to play a role in the disease.
-do not definitively demonstrate cause and effect


What are two types of inheritance

• Mendelian single-gene monogenic disorders.

• Multifactorial disorders where the phenotype is determined by variations at a few or many different loci.


Mendelian monogenic inheritance

• Single gene.
• Phenotype is determined by a mutation at an individual locus that is inherited in the simple manner as described by Gregor Mendel.



-the proportion of individuals carrying the allele who display the phenotype.
-expression frequency of an allele when it is present in the genotype of an organism.


Huntington’s chorea

- Penetrance of Huntington’s chorea/disease depends on the number of trinucleotide CAG repeats carried by the individual and by their age
- VNTR (variable number of tandem repeats) results in the expansion of the CAG trinucleotide microsatellite.
• When the number of repeats reaches a certain threshold, it produces an altered form of the protein, called mutant Huntingtin protein (mHtt), that contributes to pathological changes which result in neurological disease symptoms of Huntington’s chorea including involuntary writhing movements (chorea), congnitive decline, and psychiatric symptoms


Huntington’s chorea number of trinucleotide CAG repeats required for penetrance

• <28 repeats: normal, no disease
• 28-35 repeats: intermediate, no disease
• 36-40 repeats: low penetrance, +/- disease
• >40 repeats: full penetrance, disease present


Huntington’s chorea
how is inherited

• Autosomal Dominant
• Infected person typically inherits from an affected parent one copy of the gene (mutant allele) which produces an expanded trinucleate repeat.
• Each offspring of an affected individual has a 50% probability of inheriting the mutant allele and therefore being affected with Huntington’s chorea.


Another example is the penetrance of phenylketonuria

-autosomal recessive and person needs to be homozygous for allele to develop this disease.
-Phenylalanine in infants diet (breast milk and cows milk contain phenyalanine) triggers penetrance and the homozygous person develops brain damage/mental retardation.
- Fortunately, lack of this enzyme can be detected in the newborn screen, and rigorous nutritional (phenylalanine free diet) intervention enables the person to develop normally.


Heterozygote advantage in phenyketonuria

-So from the perspective of reduced likelihood of cross-placental infection with mycotoxin, incomplete dominance is expressed and there is a heterozygote advantage.
-pregnant: reduced likelihood of aborition and cross-placental infection


Other causes of variable penetrance

• Presence of additional SNPs affecting the promoter of the gene, rather than the coding sequence, which might affect transcriptional activation of the gene product.
• Epigenetic modification of the promoter due to developmental and environmental factors can effect gene expression and thus can be reflected in the variable penetrance.


1st reason why alleles that cause monogenic disease persist in population: recurrent spontaneous mutations Hemophilia: recessive sex-linked X chromosome disorder

• Mother and father have two daughters & two sons
• Mother is carrier of hemophilia allele
• Father is unaffected
• One son is unaffected
• One daughter is unaffected
• One daughter is carrier of hemophilia allele
• One son is affected with hemophilia
-random mutation
-female has to have both xx on to have hemophilia


Reasons why alleles that cause monogenic disease have not been eliminated from the population

• Recurrent mutation may retain a deleterious allele in the population (e.g., some forms of hemophilia).
• Effects of the deleterious allele may not become apparent until after peak reproductive age (e.g., Huntington’s chorea).
• Heterozygote advantage (e.g., sickle cell disease, cystic fibrosis, Tay-Sachs, phenyketonuria).



is mass of genetic material located in nucleus of cell composed of DNA and proteins that condense to form chromosomes during eukaryotic cell division; during prophase of mitosis, chromatin fibers become coiled into chromosomes with each chromosome having two chromatids joined at a centromere



- is one of the two copies of DNA making up a chromosome, which are joined at their centromere, for the process of cell division.



- is region on chromosome that joins two sister chromatids and is point of attachment of spindle fibers.


-what are the nucleosome composed of
-what are histone octamer composed of.. Histone proteins...

• Fundamental repeating units that contain eukaryotic chromatin.
• Each nucleosome is composed of a little less than two turns of DNA wrapped around a set of eight proteins called histones, which are known as a histone octamer.
• Each histone octamer is composed of two copies each of the histone proteins H2A, H2B, H3, and H4.



• Simple proteins containing mainly basic amino acids present in eukaryotic cell nuclei which package and order the DNA into structural units called nucleosomes.
-H2A, H2B, H3 and H4


Factors that influence phenotype:

• Polyphenism: the capacity of a species or single genotype to develop two or more forms, with each specific form depending on specific environmental conditions.
• Polymorphism refers to multiple forms encoded by two or more genotypes; the presence in a population of two or more variants (alleles or haplotypes).
• Allelic effect: the magnitude of the effect on the trait of different alleles at each locus.
• Epistatic effects: the phenomenon where the effects of one gene are modified by one or several other genes at different loci.
• Pleiotropic effects: the extent to which individual genes affect more than one trait.
• Epigenetic effects: do not change the nucleotide base sequence of DNA, but can influence the expression of genes.



-the study of changes in the phenotype or gene expression caused by mechanisms other than changes in the underlying DNA nucleotide sequence.
-epigenetic effects can influence structural changes in DNA-associated proteins which influences gene expression, without altering the nucleotide sequence
-Epigenetic signals are responsible for the establishment, maintenance, and reversal of metastable transcriptional states that are fundamental for the cell’s ability to “remember”past events, such as changes in the external environment, or developmental clues.
-lack of identified genetic determinants and inability to pinpoint causative genetic effects in some complex diseases, suggests possible epigenetic explanations for these complex traits and disease


Complex epigenetic states are orchestrated by several converging and reinforcing signals, including:

• DNA methylation
• histone modification
• noncoding RNAs
• transcription factors
• prions


diseases it is responsible for

-A non-microbial transmissable agent composed of protein in a misfolded form.
-Prions are responsible for the fatal transmissible spongiform encephalopathies in a variety of mammals, including bovine spongiform encephalopathy (BSE, also known as "mad cow disease") in cattle and Creutzfeldt–Jakob disease (CJD) in humans.
-unusual form of epigenetics
-With intimate ties to protein homeostasis and a remarkable sensitivity to stress, prions are a robust mechanism that links environmental extremes with the acquisition and inheritance of new traits.


Histone modifications cause epigenetic changes

• Acetylation.
• Methylation.
• Ubiquitination.
• Phosphorylation.
• These modifications affect the‘tails’ of the histone
proteins that protrude from the nucleosome.
• This alters their charge that can influence how tightly the DNA is wrapped around the histones, which influences access to transcriptional factors.


DNA methylation

• DNA methylation occurs on cytosine bases only where they have guanine at the intermediate 3’location = cytosine-guanine (CpG) dinucleotides.
• The p in CpG stands for phosphate.
• Many of these CpGs are clustered 5’
to the start site of the gene (Fig. 4.5)
• The conversion of cytosine to 5-methylcytosine alters the tertiary structure and thus the conformation of the DNA strand and this change, once induced, may be long lasting (some have suggested that this conformation should be regarded as the ‘5th base’ of the genome).
• Specific binding proteins may target the methylated CpG dinucleotides.
• The conversion of cytosine to 5-methylcytosine causes an alteration of access of transcriptional factors to DNA-binding sites, and depending on whether a transcriptional factor is stimulatory or inhibitory, gene expression may be increased or decreased.


Histone modifications versus DNA methylation

• Histone modifications appear to be more labile whereas DNA methylation appears to be more stable and thus involved in more sustained changes in an epigenetic state.


Example of epigenetic modulation of gene expression BOLD

*Active gene with unmethylated CpG dinucleotide in gene promoter.* This enables transcription factors (TF) and RNA polymerase (Pol) to bind to their specific nucleotide sequences and transcription of coding sequences (exons) occurs.
DNA methyltransferase produces methylation of CpG

>*Gene with methylated gene promoter.*
¯ recruit histone modifying enzyme (MeCP2-HDAC-HMT) complexes

>*Enzyme complex (MeCP2-HDAC-HMT) removes acetyl groups from histones and catalyzes methylation.*

>*Inactive gene with methylated promoter gene with methylated histone* which causes the chromatin strand to adopt a‘tighter’ conformation, preventing access of transcription factors and RNA polymerase to the DNA which silences transcription.


Epigenetics & cellular differentiation

• The cells in a multicellular organism have identical DNA sequences, yet maintain different terminal phenotypes e.g., nerve cells, hepatocytes, skin cells.
• Totipotent stem cells become the various pluripotent cell lines of the embryo which in turn become fully differentiated cells.
• The differentiation into various cell types proceeds by activation of some genes and inhibition of others through epigenetic mechanisms.


Cell potency BOLD

• The potency of a cell specifies its differentiation potential, or potential to differentiate into different cell types.


Totipotent definition BOLD
Examples of totipotent

• *Totipotency* is the ability of a single cell to divide and produce all the differentiated cells in an organism, including extraembryonic tissues.
• In humans, the *zygote, blastomere,* and the *morula cells* are all examples of totipotent cells.


Early embryonic sequence

• Day 0: conception with zygote formation
• Day 1: two blastomere cells
• Day 2: four cells
• Day 3: morula (16-32 cells)
• Day 4: early blastocyst (enters into uterine cavity)
• Day 5: late blastocyst
• Day 6: blastocyst reaches uterine wall and zona pellucida
• Day 7: implantation begins
• Day 9: embryonic bilaminar disc (epiblast and hypoblast)
• Day 11: implantation complete with amniotic cavity, yolk sac,
and uterine sinusoids
• Day 15: first missed menses/positive pregnancy test
• Day 16: trilaminar embryo with endoderm, mesoderm, and


The Embryonic Period
Week 1

• *Week 1*: pre-implantation embryo moves through oviduct to surface of uterus endometrium as blastocyst with *inner cell mass* by the end of week 1


Pluripotent cells

• *Sources of pluripotent cells* include the *inner mass cells* within the blastocyst and the *epiblast layer* within the embryonic bilaminar disc.
• Pluripotent embryonic stem cells differentiate into endoderm, ectoderm, and mesoderm which can then collectively develop all the fetal and adult body cells and tissues.
• However, alone pluripotent cells cannot develop into a fetal or adult animal because they lack the potential to contribute to extraembryonic tissue, such as all the placenta tissue.


The Embryonic Period: Week 2

•*Week 2*: implantation occurs and two layered embryonic disc (*epiblast and hypoblast*) forms from inner cell mass

LOOK AT SLIDES page 170-171


Pluripotent cells

• *Pluripotency* refers to a stem cell that has the potential to differentiate into any of the *three germ layers: endoderm*
(interior stomach lining, gastrointestinal tract, the lungs), *mesoderm* (muscle, bone, blood, urogenital), or *ectoderm* (epidermal tissues and nervous system).


The Embryonic Period: Week 3

• *Week 3*: three layered embryo (*ectoderm, mesoderm, and endoderm*) develop from epiblast layer


Multipotent progenitor cells

• *Multipotent* progenitor cells have the potential to give rise to cells from multiple, but a limited number of lineages.
• An example of a multipotent stem cell is a hematopoietic cell — a blood stem cell that can develop into several types of blood cells, but cannot develop into brain cells or other types of cells.


BOLD definition

• At the end of the long series of cell divisions that form the embryo are cells that are terminally differentiated, or that are considered to be permanently committed to a specific function.


DNA methylation role in cell differentiation

• DNA methylation silences the expression of specific genes during the development and differentiation of cells and tissues.
• Pluripotent stem cells are influenced by epigenetic changes at the appropriate time.
• The difference between two cell types from the same individual is the epigenetic profile determining which genes are expressed and under what conditions.


Epigenetic regulation immediately following fertilization

• Widespread removal of epigenetic marks occurs following fertilization, when maternal and paternal genomes undergo extensive demethylation to ensure totipotency of the developing zygote.
• This is followed by de novo methylation in specific areas just prior to implantation.
• About 70% of CpGs are methylated, mainly in repressive heterochromatin regions and in repetitive sequences such as retrotransposable elements.


Gene-promoter methylation use in development

• Assymetric silencing of parentally imprinted genes.
• Silencing retroposons, some of which are viral DNA that have invaded the human genome.
• Silencing the expression of specific genes during the development and differentiation of cells and tissues.


DNA methylation role in cell differentiation

• The expression of the homeobox (Hox) gene Oct-4, a key regulator of cellular pluripotency in the early embryo, is permanently silenced by hypermethylation of its promoter around embryonic day 6.5 in the embryo mouse.
• The expression of HoxA5 and HoxB5, which are required for later stages of development, are not methylated and silenced until early postnatal life.
• For some genes there appear to be gradations of promoter demethylation associated with developmental changes in the role of the gene product.
• The d-crystalline II and PEPCK promoters are methylated in the early embryo, but undergo progressive demethylation during fetal development and are fully demethylated and expressed in the adult.
• Thus functional changes in different cell lineages are established at different times during the development of the embryo and fetus.


‘Epigenetic memory’of patterns of DNA methylation influenced gene regulation

• The established pattern of DNA methylation is copied during mitosis by DNA methyltransferase 1 activity.
• This provides an ‘epigenetic memory’ of patterns of gene regulation, and hence cell type and function, which once established during development is passed through subsequent cell divisions.
• The same processes can inform the regulatory systems in these cells.
• This suggests a mechanism by which the environment may induce stable changes to cell function which persist into adulthood, and by which environmental changes at different times during development may produce different phenotypic outcomes with different risks for diseases.


Barr Body formation through X
chromosome inactivation

• X chromosome is much larger than Y chromosome.
• In 46:XX females, one X chromosome is shut down in 10-49% of her diploid cells.
• This inactivation of the some of the X chromosomes is by a form of chromosome-wide epigenetic suppression.
• This has apparently evolved to maintain an equivalent gene dosage in both males (XY) and females (XX).


Genetic imprinting

-The expression of certain genes that are imprinted so that whether or not they transcribed in the embryo depends on whether they are inherited from the mother or father.
• Most genes are not imprinted and both the maternal and paternal copies of the gene are actively expressed.
• Imprinted genes are expressed in a parent-of-origin specific manner; only one parental copy is expressed while the other copy is silent.
• In some imprinted genes only the maternal copy is expressed (e.g., H19 or CDKN1C), while in other cases only the paternal copy is expressed (e.g., IGF-2).
• Genomic imprinting is an epigenetic process most frequently mediated by allele-specific DNA methylation, although imprinted alleles may differ in other ways e.g., histone modifications.
• Achieves non-allelic gene expression without altering the genetic sequence.
• These epigenetic marks are established in the cell-line and are maintained through all somatic cells of an organism.


Syndromes caused when genomic imprinting is altered, because of the disruption of normal epigenetic marks that regulate imprinted genes in a particular region.

• Beckwith-Wiedemann syndrome
• Prader-Willi Syndrome


Altered genomic imprinting causes Beckwith-Wiedemann syndrome

• In healthy humans, only the paternal allele is expressed on 11p15, while imprinting causes the maternal allele to be silenced.
• Beckwith-Wiedemann syndrome is due to biallelic (paternal & maternal) expression of insulin-like growth factor 2 (IGF-2), whereas under normal conditions only the paternal allele is expressed.
• Many patients with Beckwith-Wiedemann syndrome have abnormal DNA methylation in different areas of 11p15, meaning that normal epigenetic marks that regulate imprinted genes in this region are altered (European Journal of Human Genetics,2010, 18:8–14).
• Results in an overly large neonate with large tongue (macroglossia), hyperinsulinemia and secondary hypoglycemia.
• Increased incidence in offspring conceived by assisted reproductive techniques e.g., in-vitro fertilization.


Prader-Willi Syndrome

In healthy people, in the genes on chromosome 15 that affect Prader-Willi Syndrome, it is the paternal copy that is usually expressed, while the maternal copy is silenced through genetic imprinting.
• If the paternal contribution to these genes on chromosome 15 is lost, the result is Prader-Willi syndrome.
• This means that while normal people have a single working copy of these genes, people with Prader-Willi syndrome have no working copy (both copies are silenced)
• Hypotonia
• Hyperphagia
• Obesity
• Hypogonadism
• Small hands and feet
• Mild mental retardation


Epigenetic marking in human twins

-Identical twins have identical genomic DNA.
• However, these twins have different patterns of DNA methylation and they become more different as they get older (Box 4.4).
• The increase in DNA methylation with age can result in a difference in number of differentially expressed genes of younger and older twin pairs.
• This illustrates how different phenotypes can arise from the same genotype, with the contribution of epigenetic modification of the process.


Intergenerational effects

• Most epigenetic marks are erased during gametogenesis and embryogenesis.
• However, there are human examples of disease risk related to environment being passed across several generations.
• Represents a non-genomic form of biological inheritance.


Suggested form of epigenetic inheritance

• Epigenetic marks clearly are maintained through mitosis, and there is some limited evidence that they can be maintained through meiosis.
• Micro-RNAs are present in both sperm and ova and these may be the mode of mark transmission allowing methylation and histone changes to be re-established in the next generation.


Ovarian oogonia, oocytes, &
follicle numbers through life BOLD

• Number decreases with age because of *follicular atresia* and *ovulation*
• *8 weeks gestation:* 600,000 oogonia
• *5 months gestation:* 7 million oogonia
• *Birth:* 1 million (most are primordial follicles with
• *1 year old:* ovaries contain some tertiary follicles
• *Puberty*: 500,000 follicles with oocytes
• *25 years old* 250,000 follicles with oocytes
• *35 years old:* 16,000 follicles with oocytes
• Decline in follicle number accelerates in late 30s
• *Menopause:* 0 - few follicles


Spermatogenic cells

•* Spermatogenic* cells produce 400 million sperm per day in adult males
• *Spermatogonia* are stem cells which are positioned on the basal lamina in seminiferous tubules of the testes
• As these cells move inward toward the lumen, they differentiate sequentially into *primary spermatocytes, secondary spermatocytes, spermatids* and finally *sperm*
• This process takes around 75 days
• Sperm production begins at puberty


Epigenetic mechanisms through RNA

• These changes can be copied through mitotic cell division.
• There is some evidence that under some circumstances, they can persist unchanged through meiosis, creating a non-genomic form of transient inheritance, which in some cases is expressed in a limited number of generations.
• When these changes persist through meiosis, the mechanism is thought to be through RNA.


A small RNA perspective on gametogenesis, fertilization, and early zygotic development

• Maintain genome integrity in the gametes and zygote.
• Assess the compatibility of parental genomes at fertilization.
• Promote long term memory of the zygotic epigenetic landscape by affecting chromatin.
• Transient populations of cis- and trans-acting small RNAs have recently emerged as key regulators of extensive epigenetic changes taking place during periconception, which encompasses gametogenesis, fertilization, and early zygotic development.


Cis- and Trans-acting Elements

• *Cis-element* is a region of DNA or RNA that regulates the expression of genes
• *Trans-element* is factor that binds to the cis-acting sequences to influence gene expression


Intergenerational effects

• Experimental studies in animals shows that blood pressure, heart dimensions, metabolism, and HPA (hypothalamic-pituitary-adrenal) axis settings can be altered by endocrine or nutrition of their grandmothers, without further environmental challenges to the intermediate generation (their mothers).
• The relationship between risk of adult diabetes in men and the nutritional environment of their grandfathers before puberty.
• There is higher adiposity in grandchildren of people exposed to famine in the Western Netherlands at the end of the Second World War


Suggested form of epigenetic

• The female gametes (ova) are all formed in the human female when her ovaries develop while she is still a fetus.
• Thus, a nutritional challenge to a woman during pregnancy can not only affect the developmental plasticity of her fetus, but also potentially produce epigenetic effects in her fetus’s own ova which contribute directly to the epigenome of her grandchildren, effectively conferring two generations of epigenetic inheritance through the female in the intermediate generation.


Evolutionary developmental biology (EDB) = evo-devo

• Seeks to understand mechanisms by which development has evolved, both in terms of developmental processes and evolutionary processes.
• Developmental processes: what novel cell or tissue interactions are responsible for novel morphologies in certain taxa.
• Evolutionary processes: what selection pressures promoted these novel morphologies.
• Do developmental trajectories that produce phenotypes bias the production of variation or constrain trajectories of evolutionary change.


Developmental responses to environmental cues

• Not all environmental stimuli induce a plastic response.
• Some stimuli actually disrupt the normal pattern of development.
• Other stimuli trigger the phenotype to be better matched for the environment


Critical time-frame windows for developmental plasticity

• Depend on the nature of the cue and the organ system involved.
• For example, rat neurogenesis is largely complete by 3 weeks gestation, which is about the time of birth; hence cues have much less of an impact on neuronal number if they are after this time.
- In rats there is a critical period between day 1 and 5 of neonatal life when exposure of the XX female brain to testosterone will lead to it being masculinized, and the XX rat will grow up with some male-like reproductive behavioral and neuroendocrine characteristics


Developmental responses to
environmental cues from mom

• Developing mammals obtain information about their environments through their mothers in the form of nutrients, hormones, and other substances that cross the placenta or are passed to the infant in breast milk.
• Mother’s nurturing behavior, psychological state, and stress level during gestation and breast feeding influence the development of the fetus/infant.
• These cues from the environment can generate epigenetic effects on fetus/infant.


Severe environmental influences can disrupt development by interfering with processes of:

• Gene expression.
• Cell maturation.
• Cell migration.



• The study of abnormalities of physiological and anatomical development.
• This can include not only embryonic and fetal stages, but also other developmental stages including puberty.


Types of Teratogens

• Environmental influences
• Pharmaceuticals e.g., thalidomide and diethylstibesterol
• Infections e.g., rubella, zika virus
• Folate vitamin deficiency


Pharmaceutical teratogen: thalidomide

• Thalidomide was given to pregnant women in Europe for morning sickness between 1957-1961.
• The USA FDA refused approval of this drug stating it required more testing.
• More than 10,000 children whose mothers had taken this drug, were born with phocomelia which is deformity of limbs.
• British Medical J. 1962 December 1; 2(5317): 1447–1448.


Environmental teratogen: diethylstilbestrol (DES)

• Synthetic, non-steroidal estrogen was given to pregnant women to prevent miscarriages.
• Association of mother being treated in the 1st trimester of pregnancy and her female offspring (DES daughters) developing a rare cancer, clear cell adenocarcinoma of the vagina mainly from the ages of 14-22.
• DES daughters also have a 2.5% increase in breast cancer


Infectious teratogen: rubella

• Rubella infection of a pregnant women in first 20 weeks of pregnancy can lead to the virus going across the placenta and infecting the embryo/fetus.
• Rubella infection can result in congenital rubella syndrome which can include deafness, blindness, heart abnormalities, interference with long bone growth, and mental retardation.


Folate deficiency affect on
pattern forming genes

• Neural tubes close in the early weeks post conception.
• Folate deficiency in embryos before neural tube closure increases the likelihood of neural tube defects e.g., spina bifida and anencephaly.
• It appears that this nutritional deficiency in the embryo may affect the expression or action of pattern-forming genes.
• Folic acid supplement is recommended for all pregnant women.


Spina bifida

• Spina bifida in fetus and newborn is associated with pregnant mothers who have low levels of serum folate.
• This woman’s serum folate was checked and found to be well below normal levels



• *Polymorphism* refers to multiple forms encoded by *two or more* genotypes.
• The presence in a population of two or more variants (alleles or haplotypes).
• The existence within a population of two or more genotypes, the rarest of which exceeds some arbitrarily low frequency (say 1%).



• *Polyphenism:* the capacity of a species or *single genotype* to develop two or more forms, with each specific form depending on specific environmental conditions or cues, such as temperature or day length.
• A classic example of this is the female bee which is polyphenic with two forms: the queen bee and the worker bee which are genetically identical and the phenotypic difference is induced by different nutritional exposures in an early larval stage.
• A queen bee develops if at the earliest larval stage it is fed exclusively on royal jelly.
• If not fed royal jelly it develops into a worker bee.
• The royal jelly is produced if the queen is aging or has died


Phenotype plasticity

-rapid changes in the phenotype that are irreversible
-Capacity of organisms or cells to alter their phenotype in response to changes in the environment; usually this capacity is assumed to be adaptive.


Phenotypic evolution

• Variation in most features is based on allelic variation at several or many loci, as well as direct effects of the environment.
• Many characteristics are complex and their functions depend on the coaction of several component features.


Components of genetic architecture

-genetic architecture is genetic basis of a trait and its relationship to other traits
-allelic effect
-epistatic effects
-pleiotropic effects


Allelic effect definition

-The magnitude of the effect on the trait of different alleles at each locus.



• A type of gene interaction in which one gene alters the phenotypic effects of another gene that is independently inherited.
•* Epistasis* is the phenomenon where the effects of one gene are modified by one or several other genes, which are sometimes called *modifier genes.*
• The gene whose phenotype is expressed is called *epistatic,* while the phenotype altered or suppressed is called *hypostatic.*
• Epistasis can be contrasted with allelic effect, which is an interaction between alleles at the same gene locus.



• *Pleiotropy* occurs when a single gene influences multiple phenotypic traits or characters.
• Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously.
• This can become a problem when selection on one trait favors one specific version of the gene (allele), while the selection on the other trait favors another allele.


Heterochrony BOLD

the development of the timing of the appearance of a feature is altered in relation to other features.


Neoteny BOLD

the slowing down of rate of development.


Hypermorphosis BOLD

a prolongation of time for development of a feature leading to its relative


Norms of reaction BOLD

• The norm of reaction of a genotype is the set of phenotypes a genotype is capable of expressing under different environmental conditions.
• For every genotype, phenotypic trait, and environmental variable, a different reaction norm can exist.


Graphical representation of reaction norm
what does x & y mean on graph
obesity and insulin

• X axis represents environmental conditions during development (i.e. maternal nutrition during pregnancy).
• Y axis represents magnitude of trait.
• Obesity and insulin resistance reaction norms are similar because these physiological processes are related


Maternal nutrition affects on
fetal environment

• Maternal over-nutrition and weight gain during pregnancy influence the developing fetus to have a greater likelihood of developing obesity and insulin resistance later in life.
• Maternal under-nutrition, working through different mechanisms, also influences the developing fetus to have a greater likelihood of developing insulin resistance and visceral obesity later in life.


Non-plastic reaction norm

• A non-plastic reaction norm is when phenotypic trait is fixed across the range of developmental and environmental influences.



• The evolution of internal factors during development that reduce the effect of perturbing environmental and genetic influences, thereby constraining variation and consistently producing a particular phenotype.
• For many characteristics, the most adaptive norm of reaction may be a constant phenotype, buffered against alteration by the environment.


Stabilizing selection

• Stabilizing selection refers to a tendency to select against extreme phenotypes meaning that for a given trait the bulk of variation is clustered around an average phenotype and therefore expression of genetic diversity in the phenotypes is reduced.


Genetic assimilation

• A character state that initially developed in response to the environment and becomes genetically determined.


Genetic assimilation in Drosophila

• Famous experiment by Waddington subjected Drosophila to heat shock during development which triggered the formation of different vein patterns in their wings.
• After several generations of selection the trait was expressed without exposure to high temperatures.
• Waddington termed this process as genetic assimilation.
• Waddington interpreted the initial expression of wing deformity as a disturbance of canalization due to the fact that the heat treatment shifted the trajectory of development onto a new course.
• Environmental stress caused fixation of this new course as the result of the strong selection for the new phenotype.


Adaptive responses in development

• In both plants and animals the phenotype can be altered in response to exposure of key environmental influences early in development.
• It appears that natural selection has favored the development of such plastic systems because they offer the potential for adaptive advantage in response to environmental cues.
• This enables a genotype to produce many possible phenotypes and their range will change as the environment changes.


Types of adaptive responses

•*Immediate adaptive responses:*
responses that the organism must make to survive an immediate developmental or environmental challenge which would otherwise threaten its survival.
• *Anticipatory/predictive adaptive responses*: responses that are made for anticipated need or advantage later in life course.


Immediate adaptive responses
to oxygen shortage in fetus

• As a fetus develops, it gains many homeostatic capacities which operate before birth, particularly in late gestation.
• For example, if confronted with a shortage of oxygen due to a temporary compression of the umbilical cord, it will reduce limb movements and it will redistribute blood in an attempt to maintain oxygen delivery to the brain, heart, and placenta, all essential for its immediate survival.


Immediate adaptive responses

• The more severe immediate adaptations in the intra-uterine environment allow for survival but may leave the individual with a potentially disadvantageous phenotype with which they must cope for the rest of their life.
• So the trade-off to survival may be long term consequences.


Immediate adaptive responses to reduced nutrition for fetus

• Minimize growth reduction of most immediately essential organs (e.g., heart, brain, placenta) by reducing the growth of less immediately critical organs such as the kidney.
• Tradeoff is being born with smaller kidneys and fewer nephrons increases the risk of developing renal hypertension later in life, however fitness related to hypertension may not be reduced if its affects are in post-reproductive years.
• Reduced fetal growth may also impair the development of the pancreatic islets and muscle tissue.
• Pancreatic insulin secretion may be affected.
• Glucose uptake by muscle may be affected which results in insulin resistance and type 2 diabetes later in life.
• Increased risk of developing both insulin secretion deficiency and insulin resistance in muscle and fat tissue increases risk for development of diabetes mellitus.


Immediate adaptive responses
to reduced nutrition for fetus

*Causes of reduced nutrition*:
• Famine.
• Maternal diet deficient in nutrients.
• Preeclampsia which diminishes placenta function.
*Immediate adaptive response*:
• Reduce fetal growth to survive.
*Consequences of immediate adaptive response:*
• Results in low birth weight which increases neonatal and child mortality (Fig. 4.3).
• Increases risk of developing obesity, insulin resistance, type 2 diabetes mellitus and hypertension later in life.


Neonatal mortality in USA in relationship to birth weight

• Inverse relationship of birth weight and mortality up until around 7.5 pounds
• Direct relationship between birth weight and mortality above 8.5 pounds


Immediate adaptive responses to reduced nutrition in adult females

• Under severe famine conditions, if the females fat level decreases to below 22% she may not be able to ovulate.
• This could be seen as an evolutionary response to delay possible conception until conditions are more optimal.
• However, under famine conditions where the nutritional environment is sub-optimal for the mom, conception and pregnancy can occur.
• In fact, in humans during famine conditions, lactation is often remarkably well sustained which suggests that the mother is equipped to sacrifice her own resources to meet the evolutionary drive to reproduce and feed her offspring.


Immediate adaptive responses to reduced nutrition in adult females Tradeoffs

• There is a trade-off between delaying reproduction with the expectation of better conditions later versus not delaying reproduction and conceiving when conditions are sub-optimal which results in the fetus/infant experiencing the disadvantages of reduced nutrients and weight.


Limiting growth conditions can influence final adult height

• Limited nutrition intake which may be associated with food scarcity or when there is available food but presence of frequent infant diarrhea and/or respiratory infections.
• Under conditions of sustained reduced nutrient intake first the weight growth rate drops, then the height growth rate drops, and last to drop is the head circumference growth rate.
• Stunting of growth in infants and children is a major problem in economically developing countries.
• Physical and mental capacities of these individuals can be diminished through associated effects on cognitive abilities which influence school performance and educational achievement.


Limiting growth conditions in early years post-birth can influence weight & height growth rates

• 1st decline: decrease in weight growth rate.
•2nd decline: decrease in height growth rate.
• 3rd decline: decrease in head circumference growth rate.
• This is an example of an *immediate adaptive
response* being triggered that protects the brain at the expense of weight and height.
• Only under very severe conditions of malnutrition does the head circumference growth rate decrease


Increase in height with improvements in nutrition & hygiene

• A well documented feature of human migration from poor circumstances to nutritionally richer and hygienically cleaner public health environments (which results in less diarrhea) is an intergenerational increase in height which can be quite substantial.
• Mayan children living in the USA are over 10 cm taller than their genetic counterparts living in Guatemala


Anticipatory/predictive adaptive responses

• Developmental responses of fetus or neonate for predicted long-term advantage.
• These anticipatory responses are hypothesized to be metabolic trajectories programmed by the fetus or neonate in response to how it interprets the current environment as a predictor of the future environment (i.e., what future environment is anticipated)
• The growing organism anticipates or forecasts its future on the basis of nutritional, hormonal, and other environmental signals it receives from its mother and father, either in utero, during lactation, and in childhood and adjusts its phenotype accordingly.
• *Vertical black arrow* represents the developmental trajectory defined by the fetal genome and the epigenome.
• Maternal cues, such as undernutrition during gestational development cause the fetus to shift its developmental trajectory through an epigenetic mechanism to match the perceived environment (*vertical gray arrow*).
• If the inducing environment accurately anticipates/predicts the later environment (*white background*), then the risk of disease is low.
• If there is a mismatch between the anticipated/predicted later environment and the actual later environment (*black background*), then the phenotype is vulnerable and risk of disease is enhanced.
• Fetus responds to information over a longer timescale than just a single point in time.
• The pregnant and lactating mother acts as an integrating transducer of environmental information and the fetus adjusts its phenotype for an average environment rather than responding to every minor change in maternal condition.
• These predictive responses are integrated responses affecting multiple components of the phenotype.
• The fetus and infant receives maternal nutritional cues or cues related to maternal ‘stress’via the HPA (hypothalamic-pituitary-adrenal) axis that can lead to alterations in endocrine, cardiovascular, metabolic, and reproductive function, and the development of adipocytes and myocytes.
• This period of plasticity may vary according to the physiological system involved and in humans extends from conception through breast feeding and into childhood.
• Predictive adaptive responses and immediate adaptive responses may be triggered simultaneously.
• Infants born small due to immediate adaptive responses may also have modified metabolic performance as a result of predictive adaptive responses
• Environments can shift within a single lifetime and predictions made in early life may not accurately forecast later experience.
• Mathematical models have illustrated that accuracy of prediction need not be high for it to confer fitness advantage.


Developmental plasticity in the setting of evolutionary novelty

• Developmentally plastic responses are induced by external cues, and depending on the fidelity of the relationship between the cue and the future environment, there may be effects on fitness or health.
• Perceived optimal environment versus perceived threatened environment.


Perceived optimal environment: *predicted plentiful life course*

Investment for longevity:
• Commitment to repair to cells and DNA.
• Commitment to tissue reserve including neuron and nephron number.
Investment for large adult size: • Bone mass.
• Muscle growth.
Adjustments to assure survival to birth:
• Small birth size.
• Prematurity.
• Reduction in fetal skeletal and muscle mass.
Altered reproductive strategy: • Early puberty.
Adjustments to resist threatening and difficult environment:
• Altered HPA (Hypothalamic-Pituitary-Adrenal) axis.
• Altered behavior.
• Increased insulin resistance.
• Propensity to store fat.


Correct predictive responses

• The adaptive advantage of the predictive response would depend on the fidelity of the prediction.
• Correct predictions lead to enhanced chances of growth and survival to reproduce; this would be why underlying predictive processes have been selected through evolution.


Incorrect predictive responses
can result in mismatch

There are examples where fetal nutrition is NOT a reliable cue for external conditions:
• placental insufficiency.
• maternal disease not related to food shortage.
• the external environment significantly changes between birth and later life.
• This could produce a phenotype not well suited to meeting the challenges of its environment (mismatched) and thus a greater risk for disease.
• In the metabolic domain, a phenotype with an inclination toward increased insulin resistance, reduced muscle mass, and increased propensity to store fat may have an increased likelihood of developing metabolic diseases in an environment with a high caloric diet and low level of physical activity.


Types of PEM (protein-energy malnutrition)

• Kwashiorkor
• Marasmus
• Marasmic kwashiorkor


Kwashiorkor malnutrition

• name is derived from the Ga language of coastal Ghana in West Africa
• translated as "the sickness the baby gets when the new baby comes”
• reflecting the development of the condition in children who have been weaned from the breast when a younger sibling is born
• results primarily from insufficient protein intake
• in infants & children
• anorexia/poor appetite
• edema with descended abdomen: the extreme lack
of protein causes an osmotic imbalance in the gastro-intestinal system causing swelling of the gut with edema
• edema in ankles and feet
• large liver with fatty infiltrates • thinning hair
• skin problems including ulcerating dermatoses



• results primarily from inadequate energy intake but may also have low protein intake, but not as low as kwashiorkor
• in infants & children
• emaciation
• muscle wasting
• may have no edema or some edema, but not severe edema like kwashiorkor


Predictive adaptive responses: Kwashiorkor versus marasmus

• Kwashiorkor is protein-energy malnutrition in infants and children is associated with severe edema, ascites, large liver, thinning hair, and skin problems and is more likely to be fatal than marasmus.
• Marasmus is malnutrition characterized by energy deficiency, wasting, but minimal or no edema.
• Individuals who had suffered marasmus show a greater capacity to inhibit protein turnover and thus are able to better preserve muscle protein than those who had suffered kwashiorkor.
• It has been proposed that marasmus infants/children had received nutritional stress cues earlier in life that triggered both immediate and predictive adaptive responses, adjusting to living in an anticipated low nutrition environment which includes the ability to preserve muscle protein
• In contrast, it appears that kwashiorkor infants/children did not receive adequate cues to trigger them to adapt their metabolism in expectation of a low nutrition environment and were therefore not well prepared to adjust to it.
• Because a predictive adaptive response was not triggered, these children are not able to preserve muscle protein.


Epigenetics and metabolic effects

• There is growing evidence for the role of epigenetic processes in developmental plasticity and it is likely that epigenetic control of expression of key genes is responsible for alterations of metabolic set points that predispose a person to develop obesity, insulin resistance, type 2 diabetes, and earlier menarche.
• It is possible that umbilical cord blood could be evaluated to assess the epigenetic status of a newborn’s tissues to help predict a person’s future susceptibility to disease.
• Perhaps therapeutic interventions could be developed to correct metabolic set points and thus prevent the disease development.


3 year old Asian Indian Male
has chest pain and abdominal pain

-born in india and move to USA at 2.5 yrs
-breast fed
-Physical exam reveals normal heart sounds, Decreased lung sound in both lower
lung fields, Enlarged spleen palpated in left upper
quadrant of abdomen that was tender to
-radiography shows enlarged spleen and sits of inflammation in the lungs
-parents reported no hemoglobin analysis or genetic screening was done on either of them or child in India or in the USA
-high reticulocyte count indicating that bone marrow is compensating for hemoglobin by producing more red blood cells
-he was diagnosed with sickle cell
-he was treated with red blood cell transfusions and pain management


Sickle cell crisis
vaso-occlusive crisis definition BOLD
Splenic sequestration crises

-Sickle shaped RBCs are more rigid and less flexible
and therefore can obstruct capillaries and cause
tissue inflammation in different areas of the body
-caused by sickle-shapped red blood cells that obstruct capillaries and restrict blood flow to an organ resulting in ischemia, pain, necrosis and often organ damage
-acute, painful enlargement of the spleen



• The disease results from the
multiplication of Plasmodium (parasite genus) parasites within red blood cells.


Malaria BOLD

-*Homo sapiens*
-*Anopheles mosquito*
-*Plasmodium parasites*


Four main species of Plasmodium that infect humans

• Plasmodium falciparum: can cause cerebral malaria and has highest mortality rate of any species (one million cases of dead people a year)
• Plasmodium vivax
• Plasmodium ovale
• Plasmodium malariae


Classic cyclical occurrence of sudden chills and shaking followed by fever and sweating

• Plasmodium vivax and Plasmodium ovale: cycles last 4-6 hours and occur every two
• Plasmodium malariae: cycles last 4-6 hours and occur every three days
• Plasmodium falciparum can have
recurrent fever every 36–48 hours or a less pronounced and almost continuous


Treatment of malaria

• IV or IM quinine
• PO artemisinin or artesunate
• PO mefloquine
• Choloquine is seldom used anymore
because of widespread resistance
• Resistance to mefloquine and artemisinin
are starting to emerge
• Discovery of all these drugs was based on
ethnobotanical use of plants to treat malaria


Plasmodium falciparum has
infected Homo sapiens for at
least the past 10,000 years

-agriculture and larger
human settlements that resulted in more standing water for the Anopheles mosquitoes to reproduce and transmit Plasmodium falciparum.


Human mutation inactivates CMAH gene

• A mutation inactivates the CMAH gene, which codes for the enzyme CMP Nacetylneuraminic acid hydroxylase.
• This mutation is specific to the Homo lineage and is estimated to have occurred about 2.5 million years ago.
• This mutation results in all human cellsurface glycans being terminated by CMPN-acetylneuraminic acid instead of the Nglycolylneuraminic acid found in nearly all other mammals, including the great apes.


Hematological Adaptations
to Plasmodium Parasite

• Sickle cell disease
• Thalassemia
• G6PD (Glucose 6-phosphate
dehydrogenase) deficiency


Human RBC adaptations to protect against malaria: Thalassemia

• Two alleles with expression of incomplete dominance
because the heterozygous ‘carrier’ state has protection
against malaria
• One allele synthesizes normal globin chains & the other allele has mutation that diminishes synthesis of one of
the globin chains that makes hemaglobin
• Carrier rate is 18% in Maldive Islands of South Asia
• Carrier rate is 16% of the people on the Island of
Cyprus in the Mediterranean
• Alpha forms occur in West Africa and SE Asia
• Beta forms are prevalent in Mediterranean populations


Loss of Duffy antigen

-which is a protein located on the surface of RBCs and is a receptor for the human malarial
parasite Plasmodium vivax
- A high % of Africans have lost the Duffy antigen and are resistant to P. vivax
- P. vivax infects gorillas


Loss of Gerbich antigen

*-(glycophorin C) on RBCs,
which is an integral membrane protein of the RBC
and acts as a receptor for Plasmodium falciparum
• Abnormalities of RBC cytoskeletal protein, *spectrin*
can result in elliptocytosis.
• Abnormalities of adaptor protein, *ankryrin* can result
in elliptocytosis and ovalocytosis.
• Hemoglobin C
• Hemoglobin E
• Hemoglobin S


Mutations causing abnormal
RBC shape interfere with
entrance of plasmodium
parasite into the RBC

• Sickle cell
• Ovalocytosis
• Elliptocytosis


How does sickle cell protect against

• Protective against malaria because the Plasmodium parasite is not able to
penetrate and replicate in abnormal shaped RBCs.


Sickle cell mutation

• The gene defect is a mutation of a single nucleotide (single-nucleotide polymorphism/SNP) of the β-globin gene, which results in amino acid glutamic acid being substituted by amino acid valine at position 6.
• The new nucleotide alters the codon to generate valine instead of glutamic acid.
• The β-globin gene is found on short arm of
chromosome 11.



• Two different alleles are expressed as an intermediate between the two,
• A heterozygous condition in which both alleles at a gene locus are partially expressed, often producing an intermediate phenotype
• Incomplete dominance is sometimes called partial dominance or intermediate dominance
• Intermediate dominance occurs when
the phenotype of the heterozygous
genotype is distinct from and often intermediate to the phenotypes of the
homozygous genotypes
• Sickle cell is an example of this, where the heterozygous state has expression
that is sufficient enough to provide protection against malaria


Sickle cell genetics

• Typical hemoglobin = hemoglobin A
• Sickle cell hemoglobin = hemoglobin S
• Person with typical hemoglobin A (genotype
AA) is homozygous
• Person with sickle cell trait (genotype AS) is heterozygous carrier
• Person with sickle cell disease (genotype SS) is homozygous


Culture co-evolution: sickle

• Human populations in West *Africa developed agriculturalist cultural behavior to domesticate food plants* and modified their land for irrigation
which resulted in an increase in stagnant pools of
water which created environments for the Anopheles
mosquitoes to breed thus increasing the presence of
• A cultural change to the agrarian lifestyle caused an
environmental change that triggered positive
biological selective pressure to increase the allele for
sickle cell within the population to reduce morbidity
and mortality from malaria and enhance fitness via a
heterozygote advantage.


Haplotypes in sickle cell

-mutation has occurred in five
distinct haplotypes (Senegal, Benin, Cameroon, Bantu, and Arab-India haplotypes)
• These haplotypes indicate that the *mutation arose independently at least
five different times in five different geographical areas in Africa, Middle East, & Asia*


Potential causes of dramatic reduction in population
size resulting in reduction of genetic diversity in
these five different geographical locations

• Migration of small population breaking off from main
source population
• Infectious disease epidemic causes dramatic
mortality of most of population
• Famine causes dramatic mortality of most of
• Predation
• Environmental disaster causes dramatic mortality of
most of population
• War or genocide causes dramatic mortality of most of


Sickle cell in the little boy

• The sickle cell allele emerged in this boy’s ancestors environment where malaria is
• Malaria is not present in his current environment, so having the sickle cell allele offers no protection because of the mismatch between his contemporary environment
compared to his ancestors environment.


Paleolithic diet

-they were mainly hunter and gathers
-humans consumed predominantly plant foods in this time


Neolithic diet

-still plant dies mainly
-origins of agriculture.
-origins of animal domestication primarily for milk and eggs.
-origin of agriculture and domestication of animals were associated with the development of more established human settlements.


Origins of domestication of animals for milk and/or meat in Old World (Europe/Africa/Asia); humans consume milk from all the below hoofed animals except pigs

• *Pigs* (Sus) Eurasia, New Guinea, 12-13,000 years ago
• *Sheep* (Ovis) west Asia, Mediterranean, 10,000 years ago
• *Goats* (Capra) southwest Asia and Eastern Europe, 8-
9,000 years ago
• *Horses* (Equus ferus) Central Asia 6,000 years ago • *Camel* (Camelus) West, Central, & East Asia, 4,000 years ago
• *Cows* (Bos) three species from Africa, Asia, and Europe, 12,000 years ago
• *Yaks* (Bos) Himalaya Mountains
• *Chickens* (Gallus) Asia, 8,000 years ago for eggs & meat


Where is horse milk and meat consumed?

-by humans in Mongolia and Central Asia


One humped camel gensus name and when was it domesticated

- (Camelus dromedarius) from Middle East and Horn of Africa was domesticated in the Arabian Peninsula about 4,000 years ago


Two humped camel gensus name and when was it domesticated

-(Camelus bactrianus) from Central Asia domesticated (independently of the dromedary) sometime before 4,500 years ago in Northeast Afghanistan or southwestern Turkestan


Cow Husbandry

• *Europe*: pastoralists
• *East Africa* Maasai: pastoralists
• *Nepal & Tibetan Plateau:* pastoralists
• *India*: pastoralists and urban cows that, consume
discarded plant matter, and provide milk, labor, energy
• *USA & Europe today*: CAFOs (concentrated animal feeding operations) use antibiotics and growth hormone, and result in air and water pollution and E.coli infection in humans
• *England in recent times:* feeding sheep and cow brains to cows lead to mad cow disease
• *Brazil*: cattle ranches on de-forested rainforest land


what helps enhance milk production

-fedding cows Nettles (Urtica)


what accounts for the vast amount of deforestation

-cattle ranches


Lactose intolerance post breast feeding

-about 75% of the worlds population loses the ability to completely digest a physiological dose of lactose after infancy
-Cow’s, other mammals, primates and human milk are all rich in disaccharide lactose.
• The disaccharide lactose can not be absorbed across the gut wall.
• Lactase enzyme is released in the duodenum in human infants and toddlers to break down the lactose in the GI tract to produce the monosaccharides glucose and galactose which are easily absorbed across the gut wall.
• In most humans, production of the lactase enzyme is largely switched off after weaning from breast-feeding between 2-5 years of age.
• Through human evolution up until Neolithic times, humans had not consumed lactose after infancy, so there was no benefit to putting energy into further production of this enzyme.
• In Neolithic period starting around 10,000 years ago, human populations that domesticated animals for milk evolved ability to retain lactase into adulthood.


Small Intestine

• Longest portion of the alimentary canal
• Site of most digestion by enzymes and absorption
• Three subdivisions
–Duodenum (0.3 meters)
–Jejunum (2.4 meters)
–Ileum (3.5 meters)


Digestive enzymes produced by pancreas and released into duodenum to digest (break down) foods

• *Carbohydrases* e.g., *lactase* split carbohydrates into simple sugars
• *Proteases* and *peptidases* split proteins into amino acids
• *Lipases* split fat into fatty acids and glycerol
• *Nucleases* split nucleic acids into nucleotides


Lactase persistence in adults

• 81-98%: European Americans • 48%: Hispanic Americans
• 23-30%: African Americans
• 0-5%: Native Americans
• 0-5%: East Asian Americans


Lactase persistence in some populations

• In most humans, the lactase enzyme disappears after weaning from breast-feeding.
• However, human populations with a history of pastoralism (e.g., from northern European origin), have a high prevalence of a mutation in the promoter region of the lactase gene, which causes the enzyme to be expressed and released in the intestinal tract throughout life which enables people to consume and digest milk throughout life.


Lactase persistence in northern Europe

• Genetic basis for lactase persistence in this population has been traced to a single nucleotide polymorphism (C-13910➙T) in a regulatory element upstream from the lactase gene, with the T allele associating with lactase persistence.
• Age of this allele center is estimated to be about 10,500 years ago which is roughly in line with the estimate of when domesticated cattle were introduced to this region.
• This allele was not widespread in Europe prior to 10,000 years ago which suggests that positive selection for the allele was in response to the domestication of cattle for milk.


Lactase persistence in East Africa

• Pastoralist populations in East Africa also have lactase persistence.
• These populations do not carry the single nucleotide polymorphism (C-13910➙T) allele, but rather carry several other genetic changes in the same regulatory region upstream from the lactase gene, of which G-14010➙C is the most common.
• This gene appears to have achieved its present high frequency in Kenya and Tanzania within the past 3,000-7,000 years.


Lactase persistence & introduction of cattle

• The later appearance of the G-14010➙C allele in East Africa, compared to the C-13910➙T allele in northern Europe is consistent with the archeological evidence about the timing of spread of cattle domestication into these two areas.


Lactase persistence & consumption of camel’s milk

• Another lactase persistence allele appears to have arisen in Arab populations, possibly associated with consumption of camel’s milk.


Evolutionary convergence with development of lactase persistence

• These independent origins of lactase persistence are examples of evolutionary convergence (convergent evolution), wherein natural selection arrives at a similar functional trait in different populations with similar selection pressures.


Clarified Butter = Ghee

• *Clarified butter* is milk fat rendered from butter to separate the milk solids and water from the butterfat.
• Typically, it is produced by melting butter and allowing the components to separate by density.


how does it have lactase

• Traditionally made live or active culture yoghurt contains lactase produced by the bacterial cultures which results in a significant reduction of lactose levels in the yoghurt compared to milk.



• Cheese is produced throughout the world in wide-ranging flavors, textures, and forms depending on the origin of the milk, the source animal's diet, the butterfat content, whether they have been pasteurized, the bacteria and mold culture used, and the processing and aging techniques.
• Most cheeses are acidified by bacteria or fungi, which turn milk sugars into lactic acid.
• Then the addition of rennet completes the curdling.
• Ripened cheeses like cheddar contain only about 5% of the lactose found in whole milk while the cheeses that are aged longer contain almost no lactose.



• Rennet is a complex of enzymes produced in any mammalian gut to digest the mother's milk.
• Rennet contains a proteolytic enzyme (protease) that coagulates the milk, causing it to separate into solids (curds) and liquid (whey).
• Rennet also contains chymosin (rennin), pepsin and lipase.
• Vegetarian alternatives to animal rennet are available such as the fungus Mucor miehei.


what fungal mold is used to make brie cheese?

-Penicillium candidum, Penicillium camemberti or Brevibacterium linens



• Two species exert reciprocal selective pressures which affect the evolution of both.


Co-evolution between pastoralist humans and cows

• Pastoralist humans evolved lactase persistence from living with and managing cows for their milk.
• Cows were first domesticated at least 10,000 years ago and have been artificially selected for milk and meat yield and have changed dramatically because of their association with humans.


Artificial selection = selective breeding

• The human breeder of livestock is the active agent that directs mating of specific individuals to select for a trait that is intended to change in the population for a specific purpose.


A 28 year old SE Asian male presents to clinic with abdominal pain, bloating, & loose stools

• This SE Asian immigrant does not carry the lactase persistence mutation and therefore does not release lactase into his duodenum.
• The discomfort that he experiences is due to the diarrhea and flatulence induced by drinking milk.
• The unabsorbed disaccharide lactose from the milk causes an osmotic load in the gut which produces diarrhea and cramping.
• Excess gas produced by fermentation of the disaccharide sugar by intestinal bacteria causes bloating and cramping.


Is lactose intolerance normal or abnormal?

• Western medical textbooks often define the inability to absorb lactose as a metabolic disorder called adult hypolactasia and the World Health Organization (WHO) classifies such‘lactose intolerance’as a metabolic disorder.
• However, from an evolutionary point of view this SE Asian man’s inability to digest lactose is normal, in fact this is the ancestral human condition of most Homo sapiens adults.
• 70-75% of the world’s Homo sapiens adult population are not able to digest milk because their ancestors evolved in geographical regions where cow’s milk was not consumed and other rich sources of calcium and protein were available in the traditional diets.
-having the inability to consume milk after infancy could be seen as an evolutionary advantage which could lower a person’s risk of developing coronary artery disease and some types of cancer.


Pastoralists with lactase persistence Activity level & milk consumption

• Pastoralists get a tremendous amount of exercise that elevates their HDL (high density lipoprotein) levels which lowers their risk for coronary artery disease even though they are consuming a lot of milk.
• While high milk consumption in pastoralist populations can be healthful, in sedentary urbanized populations with lower HDL levels, the high milk consumption may contribute to increased rates of coronary artery disease.


Maasai pasturalists traditional diets

• Maasai pastoralists in Kenya and Tanzania walk large numbers of miles daily herding their cattle.
• These herders tend to be quite thin, tall, & healthy.
• Nutritional and ethnobotanical studies have shown that Maasai not only consume milk of the cows, but some also drain blood from the saphenous veins in the cows legs.
• The milk and blood are used in soups which also contain a variety of medicinal plants which contain a spectrum of antioxidant phytochemicals.


Transitions in Maasai diet and exercise

• Some of the Maasai are moving into urban areas and becoming more sedentary.
• Under these sedentary conditions of reduced physical activity, they continue to have a high milk consumption with increased consumption of processed foods, that results in weight increase, HDL decrease, and a rise in risk for coronary artery disease & Type 2 diabetes.
• With behavioral (level of activity) and dietary mismatches, compared to ancestral activity levels, urban sedentary Maasai have health problems.


Which Pathway(s) is/are demonstrated in this case?
SE man

• Outcome of demographic history.
• Life-history associated factors. (person is at developmental stage in which he is not able to digest lactose)
• An evolutionary mismatched or novel environment.
• Outcome of cultural evolution.


Vitamin D

• Fat soluble secosteroid
• Vitamin D2 (ergocalciferol): obtained from plant foods
• vitamin D3 (cholecalciferol): from sunlight on skin and from some animal foods and some fungi


Vitamin D2

• Synthesized by plants and can be obtained by eating these plants
• Much less potent form of vitamin D compared to vitamin D3
• Much less effective at elevating blood 25-hydroxyvitamin D levels
• Shorter shelf life than vitamin D3
• Vitamin D3 is recommended over vitamin D2 as a human supplement to maintain normal blood 25-hydroxyvitamin D levels


Sources of vitamin D3 (cholecalciferol)

• Sun exposure on skin
• Fish
• Eggs
• Liver
• UV-irradiated mushrooms and yeast are the only known significant vegan food sources of vitamin D3


Vitamin D functions

• Maintain normal blood levels of calcium and phosphorus.
• Aids in absorption of calcium by the intestine.
• Promotes healthy mineralization, growth and remodeling of bone which helps to form and maintain strong bones.
• Prevents hypocalcemic tetany.


Effects of Low Vitamin D levels

• Thin, brittle, and weak bones. • Rickets: osteomalacia in children.
• Osteomalacia in adults: softening of
bones due to defective bone mineralization which can lead to bone malformation and lower back pain and thigh pain.
• Osteoporosis in adults: reduction on bone density especially in women
• Hypertension
• Breast cancer
• Prostate cancer
• Inflammatory disease • Several autoimmune diseases • Cesarean section
• Autism


Vitamin D3

• Vitamin D3 (cholecalciferol) is synthesized from 7-dehydrocholesterol in the deep epidermis (stratum basale & stratum spinosum) of human skin when exposed to ultraviolet-B (UVB) rays from the sunlight.


Layers of Epidermis

• Stratum corneum (outer layer) • Stratum lucidum (only in thick skin)
• Stratum granulosum
• Stratum spinosum
• Stratum basale (most inner layer)


Vitamin D

• *cholecalciferol* synthesized in skin
• *calcidiol* (25-hydroxyvitamin D3) formed in liver
• *calcitriol* (1,25 dihydroxyvitamin D3) formed in kidney
• *calcitriol* is the biologically active form of vitamin D which functions as a hormone.
• *vitamin D-binding protein* binds to calcitriol and transports it in plasma to other organs
• *Calcitriol* binds to *vitamin D-binding protein*, a carrier protein in the plasma, that transports calcitriol to various target organs.


Cholecalciferol to calcidiol

• *cholecalciferol* synthesized in the skin is carried into bloodstream to the liver, where it is converted into prohormone *calcidiol* (25 hydroxycholecalciferol = 25-hydroxyvitamin D3)


Epidermis cell types

• *Keratinocytes*: most common cell type in epidermis and are full of keratin
• *Melanocytes*: location—basal layer; manufacture and secrete pigment
• *Tactile epithelial cells:* location—basal layer;
attached to sensory nerve endings
• *Dendritic cells*: location—stratum spinosum;
part of immune system; macrophage-like


Layers of Epidermis Stratum basale

• Melanocytes—spider shaped melanocytes make up 10-25% of the cells in stratum basale
• Melanocytes make melanin and transport it through its spider shaped cells process to nearby keratinocytes


Vitamin D (cholecalciferol) production

• Cholecalciferol is produced in the deep epidermis in the stratum spinosum and stratum basale.
• The melanin in the keratinocytes blocks the penetration of UV into the epidermis and shields the cell nuclei from incoming UV radiation.
• Inverse relationship between level of melanin in skin and ability of skin to manufacture vitamin D at a given UV exposure.


Melanin level as outcome of demographic history

• Humans with highest levels of melanin tend to have ancestors who originated from regions of the world (e.g., equatorial latitudes) where they have been exposed to large amounts of UV light.
• Humans with low levels of melanin tend to have ancestors who originated from regions of world north of the equator exposed to lower levels of UV light.


Melanin & UV radiation

• Darker skinned people have darker melanin and more pigment in each melanocyte.
• In all but the darkest skinned people, melanocytes respond to ultraviolet radiation by increasing production of melanin and increasing its transfer to keratinocytes, the protective response which results in a suntan.


Melanin in skin

-sensitivity of skin to UV radiation is influenced by its level of melanin.
• Most people with light skin can increase their level of melanin by moderate exposure to sun over days or weeks which stimulates increased output of melanocytes (suntan) which is an example of physiological plasticity.


Melanin in skin

- Long term exposure to different amounts of sunlight at different latitudes has created a spectrum of human skin colors influenced by the variation in the amount and type of melanin in the skin, with an almost linear relationship between latitude of population origin and skin melanin levels
• It is believed by many evolutionary biologists that the selective pressure for lighter skin color in northern latitudes arose from the need to maximize vitamin D production in the skin in areas of relatively low ultraviolet B availability.


Natural selection of melanin level

• Natural selection favors high pigmentation in areas of high sun and high ultraviolet exposure to protect against ultra-violet light skin damage and skin cancer.
• Natural selection favors decreased pigmentation in areas of low sunlight and ultraviolet exposure to increase vitamin D synthesis.


Vitamin D dark skin

• People with dark skin require up to 10 times more exposure to sunlight than people with light skin to produce the same amount of vitamin D.
• Darker skinned people who live in more northern latitudes than their ancestors, are at risk for vitamin D deficiency.


Vitamin D levels inversely related
to bone fractures in girls

• Over 9,000 girls 9 to 15 years of age were followed over a 7 year period.
• 4% of these girls developed a bone stress fracture and 90% of these girls participated in at least an hour a day of high-impact physical activity
• Girls in the group with the 20% highest intake of vitamin D were 52% less likely to develop a fracture than girls in the group with the 20% lowest intake of vitamin D.


Oral intake of Vitamin D

• 1–70 years of age: 600 IU/day (15 μg/day)
• 71+ years of age: 800 IU/day (20 μg/day)
• Pregnant/lactating: 600 IU/day (15 μg/day)
• Some nutritionalists are recommending 1,000-2,000 IU/day


Serum 25-hydroxyvitamin D3

• Serum 25-hydroxyvitamin D3 levels of 30 to 50 ng/ml are now considered to be in the desirable range by many dieticians and physicians.
• Some consider 40 to 80 ng/ml to be the desirable range.


Dietary sources of calcium

• Beans e.g. soy products
• Nuts and seeds
• Whole grains
• Leafy greens, broccoli
• Dairy products


B9 (folic acid and folate

• Important sources of folate are leafy green vegetables (e.g., kale & spinach) & some fruits e.g. oranges.
• Folate consumed in the diet is metabolized in the liver to produce bioactive metabolites.• The terms folic acid and folate are often used interchangeably for the water-soluble B9 vitamin.
• Folic acid occurs rarely in foods or the human body but is the form most often used in vitamin supplements and fortified foods and is easily bioavailable.
• Naturally occurring folates exist in many chemical forms.
• Folates are found in plant foods as well as in metabolically active forms in the human body
• People who regularly consume folate will have 500–20,000 µg of folate in body stores.
• With complete lack of dietary folate intake, it can take months before these stores are depleted.


B9 (folic acid and folate)
Essential to numerous bodily functions

• Water soluble vitamin
• Involved in synthesis, repair, and methylation
of DNA.
• Cofactor in numerous biological functions.
• Aids rapid cell division and growth, such as in
infancy and pregnancy.
• Bone marrow maturation.
• Red blood cell production.
• Development of neural tubes in embryos.



• This important vitamin undergoes photolysis when exposed to UV light, which can contribute to a folate deficiency.
• Increased skin pigmentation protects the folate from photolysis in the presence of UV light.
• Folate deficiency is less prevalent among people of African descent.
• Folate deficiency and neural tube defects are more prevalent among people with less skin pigmentation.
• There is an increased incidence of neural tube defects with maternal tanning bed use, which exposes the skin to direct UV light resulting in folate photolysis.


Folate deficiency

• Macrocytic anemia
• Impairment of DNA synthesis and repair
• Peripheral neuropathy
• Neural tube defects (e.g., spina bifida and anencephaly) in developing embryos
• Increased risk for cleft lip and palate
• A serum folate of 3 μg/L or lower indicates deficiency.
• An erythrocyte folate level of 140 μg/L or lower indicates inadequate folate status.
• Folate deficiency is treated with supplemental oral folate of 400 to 1000 μg per day or diet rich in folate.


Folate deficiency during pregnancy increases risk of

• preterm delivery
• infant low birth weight
• fetal growth retardation
• increased homocysteine level in the blood, which may lead to spontaneous abortion and pregnancy complications
• All pregnant women are recommended to take a daily oral supplement of folic acid prior to conception and throughout their pregnancy and lactation.
• Women who get 400 micrograms (0.4 milligrams) daily prior to conception and during early pregnancy reduce the risk by 70% that their baby will be born with a serious neural tube defect (a birth defect involving incomplete development of the brain and spinal cord).58


Skin melanin, vitamin D and folic acid

• Melanin in skin is inversely related to vitamin D production.
• Melanin in skin is inversely related to folic acid destruction in blood.
• High melanin levels is related to high folic acid blood levels and low vitamin D production from UVB.
• Low melanin levels is related to low folic acid blood levels and high vitamin D production from UVB.


Genetic Variation at the MC1R Locus and the Time since Loss of Human Body Hair

• Around 1.2 million years ago it is estimated that the skin of Homo erectus was dark and mainly hairless and this continued in Homo
for the next 1.1 million years until 100,000 years ago when the first Homo sapiens
started migrating out of Africa


Increase in epidermal permeability barrier

• The skin tone grew darker to increase the epidermal permeability barrier.


Increase in epidermal
permeability barrier

• Essential protective functions of the skin, including the permeability barrier and the antimicrobial barrier, reside in the stratum corneum.
• The loss of body hair likely triggered an increase in genetic change related to the stratum corneum as natural selection favored mutations that protect this essential barrier.


Human migration and skin color

• 100,000 to 70,000 years ago, as populations began to migrate, the level of skin melanin typically decreased proportionally to the distance North a population migrated, resulting in a range of skin tones from the equator up to more northern latitudes.
• Under conditions of less UV light exposure in northern latitudes, there was less photodestruction of folate.
• In addition, lighter skin is able to generate more vitamin D (cholecalciferol) than darker skin given the same UV light exposure, resulting in a health benefit and selective advantage in reduced sunlight.


Genetic Evidence for Convergent Evolution of Light Skin in Europeans and East Asians

• The SNP (single nucleotide polymorphism)
genetic mutations leading to light skin, are different among East Asians and Europeans.
• The two groups likely experienced a similar selective pressure due to settlement in northern latitudes.



• Genetic analysis of alleles undergoing clinal traits demonstrates corresponding clinal variation in allele frequencies.
• Our genotype, and consequently our phenotype, are determined by the position of our indigenous origin on a multitude of intersecting clines.
• For example in the eastern hemisphere, some clines, e.g., skin melanin, go north-south while other clines, e.g., blood type B span east-west.
• With many human characteristics/traits there is a continuous geographical gradient (cline) of a trait rather than discontinuous variation.
• Because of the north-south clines that exist for skin melanin, there is often a gradual and progressive change along a clinal gradient rather than discontinuous variation.
• Hence, the designation of race based on skin melanin is erroneous…there are no races, but only clines which demonstrate a continuous spectrum of variation within Homo sapiens.
• The continuous variation in human traits on gradients which vary in orientation means that there are no boundaries, geographical or genetic, which can be used to assign individuals to particular races….there are no races, only clines.
• Similarly, intrapopulation and interpopulation variation in disease risk tends to be clinal and not racial.
• Clinal variation can also be demonstrated within and between ethnolinguistic groups.


Benefits of pigmentation

• Pigmentation (melanin) serves to regulate the effects of UV radiation in the contents of cutaneous blood vessels located in the dermis.
• High skin melanin levels contribute to darker skin color which protects against sunburn, skin cancer, and the destruction of nutrients (e.g., folic acid) in the skin.



• Pigmentation is an adaptation to the presence of UV light that contributes to fitness by influencing vitamin D3 and folate levels in the body.


Female melanin levels

Maternal melanin levels drop during pregnancy so she can more efficiently manufacture vitamin D on her skin to aid in calcium absorption.
• Maternal calcium needs increase during pregnancy and lactation because the mother must provide enough calcium for fetal and neonatal skeleton development.
• Infants also have lower levels of melanin than older children and adults which enables them to produce more vitamin D in their skin.
• A tradeoff is that the lighter skin results in more depletion of folate in blood.
• Females have lighter skin than males, most likely to facilitate greater vitamin D3 production to aid in calcium absorption for proper bone deposition.


Selective forces on pigmentation

• Pigmentation decreases when vitamin D3 production needs are increased.
• Pigmentation increases to protect against UV damage to folate in blood as well as skin cell nuclei.
• Both vitamin D and folate are necessary for reproductive success so for good health there should be a balance between the requirements for these two nutrients.
Skin pigmentation reduces folate depletion by reducing the exposure to UV from sunlight.


Skin pigmentation effect on vitamin D3 and folate

- dec. pigmentation > in UV light exposure > inc. vitamin D3 production
- dec. pigmentation > inc. UV light exposure > inc. depletion in blood


5a european seatle women lower back pain

• Osteomalacia is softening of the bones caused by decreased bone mineralization.


Case 5a, Cause of osteomalacia

• Deficiency in vitamin D
• Diminished sun exposure to skin resulted in diminished vitamin D production in skin.
• Very low intake of vitamin D in the diet since woman is lactose intolerant and does not drink milk and does not take Vitamin D supplement


Case 5a, Which evolutionary pathway(s) is/are demonstrated in this case?

• Outcome of demographic history
• Life-history associated factors
• An evolutionary mismatched or novel
• Outcome of cultural history


• A two year old African American breast fed male from Detroit, Michigan presents with bowed legs.

• Rickets causes softening of bones in children which can potentially lead to bone deformity (e.g., leg bowing) and fractures.


Case 5b, Which evolutionary pathway(s) is/are demonstrated in this case?

• Outcomes of demographic history.
• An evolutionary mismatched or novel environment.


Causes of poor Vitamin D
levels in this child

• Breast milk is a poor source of vitamin D for infants.
• This child does not spend very much time outdoors.
• Michigan is quite cold six months out of the year and the winter daylight hours are short.
• Amount of UV radiation is significantly lower in Michigan, compared to Ghana.


Case 5c 28 year old European-American female with ancestors from northern Italy presents with enlarging dark brown lesion on skin of forearm.



Melanocytes & Melanoma

• *Melanocytes* are cells that produce the dark pigment, melanin, which is responsible for the color of skin.
• *Melanoma* is a malignant tumor of melanocytes.


Case 5c, Which evolutionary pathway(s) is/are demonstrated in this case?

• An evolutionary mismatched or novel environment:
• Outcome of cultural choice to frequently lay in the sun


Folate deficiency affect on
pattern forming genes

• Neural tubes close in the early weeks post conception.
• Folate deficiency in embryos before neural tube closure increases the likelihood of neural tube defects e.g., spina bifida and anencephaly.
• It appears that this nutritional deficiency in the embryo may affect the expression or action of pattern-forming genes.
• Folic acid supplement is recommended for all pregnant women.


Spina bifida

• Spina bifida in fetus and newborn is associated with pregnant mothers who have low levels of serum folate.
• This woman’s serum folate was checked and found to be well below normal levels.


Case 5d, Which evolutionary pathway(s) is/are demonstrated in this case?

• Outcomes of demographic history.
• An evolutionary mismatched or novel environment