Human Genome Organization

Question 1

size of haploid human genome sequence

Answer 1

3 x 10^9 bp

Question 2

Human genomic DNA is distributed on __________ chromosomes

Answer 2

46

Question 3

The chromosomes are found in __________ pairs:

1) 22 \_\_\_\_\_\_\_\_\_\_ 
2) 1 \_\_\_\_\_\_\_\_\_\_

Answer 3

23
autosomes (1-22)
pair of sex chromosomes (XX or XY)

Question 4

Each chromosome is believed to consist of a __________

Answer 4

single, continuous DNA double helix

Question 5

Human Genome

Answer 5

• is a record of human evolutionary history
• Reflects results of different selection pressures that have occurred over evolutionary time and shaped our genome (and shaped us)
• Genes and genomic features that have been adaptive have been retained

Question 6

Genotype + environment = __________

Answer 6

phenotype

Question 7

Random genomic variation

Answer 7

• is the fuel of evolution
• Random variation in a highly ordered structure = almost always deleterious consequences
• Genetic disease is the price we pay as a species to continue to have a genome that can evolve, i.e., that can adapt to new and changing environments

Question 8

The human genome is __________ and continues to evolve

• ~30 new mutations occur in each individual
• Shuffling of regions at each meiosis due to __________
• Can produce __________ DNA changes as well as __________ DNA changes

Answer 8

dynamic
recombination
somatic
germ-line

Question 9

Organization of the genome

Answer 9

• Gene-rich regions/chromosomes
• Gene-poor regions/chromosomes
• Stable regions: majority of genome
• Unstable, dynamic regions; many are disease-associated
• GC-rich regions (38% of genome), AT-rich regions (54% of genome)

Question 10

__________ (i.e. non-random distribution) of GC-rich and AT-rich regions is basis for chromosomal banding patterns (cytogenetics, karyotype analysis)

Answer 10

Clustering

Question 11

Clustering (i.e. non-random distribution) of GC-rich and AT-rich regions is basis for __________ (cytogenetics, karyotype analysis)

Answer 11

chromosomal banding patterns

Question 12

Euchromatic regions

Answer 12

more relaxed

Question 13

heterochromatic regions

Answer 13

more condensed; more repeat-rich

Question 14

Genome sequencing effort focused on __________ region

Answer 14

euchromatic

Question 15

__________ regions essentially unsequenced

Answer 15

Heterochromatic

Question 16

Genome composition

Answer 16

1) 1.5% is translated (protein coding)
2) 20-25% is represented by genes (exons, introns, flanking sequences involved in regulating gene expression)
3) 50% “single copy” sequences
4) 40-50% classes of “repetitive DNA” - Sequences that are repeated hundreds to millions of times

Question 17

Tandem repeats

Answer 17

i.e. “satellite DNAs”

Question 18

examples of tandem repeats

Answer 18

• Some are in different parts of genome, e.g. used as the basis for cytogenetic banding
• Some (a particular pentanucleotide sequence) are found as part of human-specific heterochromatic regions on the long arms of Chr 1, 9, 16 and Y (hotspots for human-specific evolutionary changes)
• “α-satellite” repeats (171 bp repeat unit) found near centromeric region of all human chromosomes; may be important to chromosome segregation in mitosis and meiosis.

Question 19

Dispersed repetitive elements

Answer 19

• Alu family
• L1 family
• Alu’s and L1’s can be of significant medical relevance

Question 20

In dispersed repetitive elements, __________ may cause insertional inactivation of genes

Answer 20

Retrotransposition

Question 21

In dispersed repetitive elements, __________ may facilitate aberrant recombination events between different copies of dispersed repeats leading to diseases

Answer 21

repeats

Question 22

Alu family

Answer 22

e. g. of SINEs: Short Interspersed repetitive Elements
- ~300 bp related members
- 500,000 copies in genome

Question 23

L1 family

Answer 23

e. g. of LINES: Long Interspersed repetitive Elements
- ~6 kb related members
- 100,000 copies in genome

Question 24

Insertion-deletion polymorphisms

Answer 24

Minisatellites

Microsatellites

Question 25

Minisatellites

Answer 25

• tandemly repeated 10-100 bp blocks of DNA

- VNTR (variable number of tandem repeats)

Question 26

Microsatellites

Answer 26

• di-, tri-, tetra-nucleotide repeats
• ->5 x 104 per genome
• STRPs (Short Tandem Repeat Polymorphisms)

Question 27

Single Nucleotide Polymorphisms (SNPs)

Answer 27

• frequency of 1 in ~1000 bp

- PCR-detectable markers, easy to score, widely distributed

Question 28

Copy number variations (CNVs)

Answer 28

• variation in segments of genome from 200 bp – 2 Mb
• can range from one additional copy to many
• array comparative genomic hybridization (array CGH)
• loci may cover 12% of genome

Question 29

Gene family is

Answer 29

composed of genes with high sequence similarity that may carry out similar but distinct functions

Question 30

__________ arise through gene duplication, a major mechanism underlying evolutionary change

Answer 30

Gene families

Question 31

Some CNV regions are involved in rapid & recent evolutionary change. Such regions are often

Answer 31

• enriched for human specific gene duplications
• enriched for genome sequence gaps
• enriched for recurrent human diseases

Question 32

Role of genome architecture

Answer 32

Link between evolutionarily adaptive copy number increases and increase in human disease

Question 33

Limitations of genome sequencing and genotyping platforms

Answer 33

Nextgen DNA sequencing and Genome-wide association studies (GWAS)

Question 34

Nextgen DNA sequencing

Answer 34

– No mammalian genome has been completely sequenced & assembled
– Nextgen sequencing relies on short read sequences
—Complex, highly duplicated regions are typically unexamined
—Such regions are implicated in numerous diseases, e.g. 1q21

Question 35

Genome-wide association studies (GWAS)

Answer 35

– “Missing heritability” for complex diseases: Many large-scale studies implicate loci (e.g. SNPs) that account for only a small fraction of the expected genetic contribution
– Many regions of the genomes are unexamined by available “genome-wide” screening technologies: is this where the “missing heritability” lies?