Chapter 4: Genome Variation Flashcards Preview

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Flashcards in Chapter 4: Genome Variation Deck (21):


Absorb CO2, one species highly heterozygous despite asexuality. All grow faster with more light but the growth rate at one light level is not a predictor of growth at other light levels. Diatoms could have changing environmental conditions. Added more iron to test: Lasted only 18 days and most of the sequestered carbon failed to sink as predicted. This is because, as you learnt from genomic analysis, populations of diatoms are highly variable and the genetic variability means different responses to environmental conditions



Single nucleotide polymorphisms (SNPs) are single bases at a particular locus that are different in different individuals. SNPs make up about 90% of all human genetic variation, occur every 1 Kb meaning a total of over a million SNPs. Majority of SNPs are irrelevant. A fraction protective/damaging


SNPs and Tasters

Phenylthicarbamide (PTC) tastes bitter to some while it has no tatste to others. Taste receptor Tas2R. If you have 3 SNPs that code three amino acids (PAV) you are a taster. If you have 2 or less you are a non-taster.


Are we from Africa? Two theories

Out of Africa: Modern humans originated in Africa and migrated to the rest of the world. Multiregional: Modern humans evolved into modern humans at different sites around the world.


Test Africa Theories

We inherit mitochondrial genome from our mothers. No recombination. This means that mutations are passed in a direct female line of descent. Similarly the Y-chromosome is almost entirely passed in a paternal line of descent. Can trace mutations in mito and Y. Amount of genetic variation is a function of both time and population size. Migrating populations carry only a small subset of the variation found in the source population. Africans have more genetic variation among themselves than non-Africans suggesting longer genetic history. Non-Africans show a subset of variants found in Africans suggesting migration from source. .


linkage disequilibrium

If two alleles (two SNPs) tend to be inherited together more often than would be predicted, we say they are in linkage disequilibrium



refers to a set of linked alleles (SNPs) on one particular chromosome. Haplotypes are inherited as a unit unless recombinationoccurs to separate them.


How to deal with polygenetic genes problem

SNP 1) focus on human populations with high instances of the disease (example P2) 2)map first region of the genome where major gene variants causing diseases reside 3)do large scale genome sequencing to find rare variants



a drug with limited efficiency in patients with non-small-cell lung cancer. The drug is more effective in Japan than America. Its efficacy depends on your genotype!


Few SNPs associate with disease

Sickle cell anemia: A single SNP results in an amino acid change in hemoglobin. •Skin pigmentation: Not known how many genes involved. An association between SNPs that inactivate MC1R gene and red-haired people with pale skin and freckles. •Malaria resistance: Nos2 promoter for nitric oxide (NO) synthase that produces cell-signaling gas NO. A SNP at Nos2 (TC) no NO in the blood and 80% less likely to develop fatal malaria. Can we regulate NO production through medication? SNP frequency in East Africa was 25%. Unknown in other populations.


Why so few SNP –disease association?

1) low freq (The problem might be on that we have only focused on common (frequent) variants. Is it possible that rare SNPs (very low frequency) are really the ones linked to disease? And even perhaps spread over several genes?) 2) population specific effects [genome projects have been missing by not sampling enough from some populations] 3) Prior focus on coding genome (Only a small portion of the genome codes for protein.


A case example of using a priori knowledge:
Heart disease

How common is variation (SNPs) in noncoding genome? 3,500 people measured for factors that can contribute to coronary artery disease phenotypic data. Concentrate on those with interesting phenotypes (e.g. high vs. low HDL and LDL levels) Focus on genes suggested from previous studies to be involved in rare disorders of cholesterol metabolism (candidate genes) Several rare SNPsat candidate genes were linked to extremely low HDL levels. Notice that rare SNPs will be extremely difficult to detect unless you have an a prioriidea of where to search . Two mutations that silence gene
PCSK9 associate with low LDL. Drug companies are now testing drugs that shut off PCSK9


de novo mutations

1,548 Islanders and parent-offspring (trios) sequenced. The number of de novo mutations increases more drastically with father’s than mother’s age. The type of genetic mutations from mother’s changes substantially with age (e.g. CG increases; CGTG decreases). The age-related changes are not uniformly distributed across the genome, with a region of chromosome 8 enriched for CG de novo mutations.


Implementing genome medicine

Prenatal and newborns [Some major progress on rare monogenic disease (2014 to present).] Cancer genomics [A complex disease. Power of GWAS. But some powerful anecdotal findings] Clinical genomics [You and your genome.]


Cancer genomics

Sequence a biopsy of the tumor and scan the genetic sequence for any abnormalities. Then match relevant abnormalities with potential treatments. Map cell and cancer stage specific mutations from patient. What are founder mutations (cancer initiators) and what are progression mutations (spread)? An example, a recent study (Nature August 2017) sequenced genomes of 500 people and compared cancer and non-cancer tissue from the same patient that informs of what goes on in each patient metastasis(personalized).


What are founder mutations and what are progression mutations ?

cancer initiators; spread



Pharmacogenomics refers to the complete list of genes that determine overall drug efficacy. Originally focused on genes that metabolized drugs but is now trying to account for other genes (transporters, receptors, signaling paths, etc).Drug response is polygenic and so genetic variation can have significant effects on drug effectiveness and safety.



It binds an enzyme (Cyclooxigenase) and acetylates a serine Cox is inactive.•If active, Cox makes prostraglandins which trigger pain, inflamation and fever.•But we have two Cox genes in our genome! •Cox-1 Mainly stomach and liver •Cox-2 brain, white blood cells, etc •Some people experience stomach problems because their stomach enriched Cox-1 are inhibitedHuman genome diversity. •You want aspirin to leave Cox-1 alone!


Gene 2D6

2 SNPs contribute to altered protein expression. The most common SNP alters splicing no protein. More than 40 different drugs require 2D6 protein activity (antiarrhytmics–heart medication, antidepressants, painkillers) Frequency of poor metabolizers is 1% in Arabs and 30% in Hong Kong Chinese


Gene 2C19

•Helps metabolize mephenytoin(used for epileptic seizures) The most common SNP creates an aberrant splice site. 2-3% Caucasians but about 23% Asians. A population-specificdosage is needed.



-a patients sequencing allows the identification of a mutation that is targetable with citrate supplements.
-Pompey disease: cannot break dow glycogen due to the mutation making enzyme deficient —>deliver enzyme (drug)
-Menkes—>mutation identifies need for cooper