Genetic Variation II

Question 1

What was the focus of the HapMap project?

Answer 1

To ultimately produce a fine scale genetic map which would serve as a common resource for all biomedical researchers.

Question 2

Which populations did the HapMap project look at?

Answer 2

4 populations:

CEPH (Europe)

Yoruban (Africa)

Japanese/Chinese (Asian)

Question 3

What was phase I of the HapMap project?

Answer 3

One million common SNPs (every 5 kb across the genome) were genotyped in 269 DNA samples from 4 populations

Question 4

What was phase II of the HapMap project?

Answer 4

An additional 4.6million SNPs are genotyped

Question 5

What is investigated in the 1000 genomes project?

Answer 5

1092 genomes are sequences including 14 populations

Whole genome was sequenced (Low coverage: 2 - 6x) and the exome (deep coverage 50 - 100x)

Question 6

What is the most recent phase of the 1000 genomes project?

Answer 6

Phase 3 which investigates 2535 individuals and 26 populations with a high coverage of both exome and whole-genome data.

Question 7

Does genetic variation have harmful consequences on people?

Answer 7

Most is neutral only some are harmful

Functional variants that are primarily studied are those that have an effect on gene function.

Estimating how much of genome is functionally important is not straight forward.

Question 8

Why is it hard to know which genes are functionally important?

Answer 8

Estimating how much of the genome is functionally important is not straight forward because even within the small target of sequences that are important for gene function, many small DNA changes may still have no effect

Question 9

What are the 2 extremes with regard to mutation and functional change?

Answer 9

Virtually all amino acids can be replaced while maintaining original function.

OR

Single mutation may give rise to completely new function

Question 10

What must be considered when more than 1 mutation is required for new function?

Answer 10

The order of mutational events.

Question 11

What does this “5162 G-A” mutation nomenclature mean?

Answer 11

5162 = Base position

G = original base

A = replacement base

Question 12

What does this “197delAG” mutation nomenclature mean?

Answer 12

197 = position

del = deletion

AG = bases being deleted

Question 13

What does this “R197G” mutation nomenclature mean?

Answer 13

R = original amino acid

197 = amino acid position

G = replacement

Question 14

What is a conservative mutation?

Answer 14

Mutation change to an amino acid that is similar to original amino acid so it results in no difference in functionality of the original protein.

Question 15

What is OMIM?

Answer 15

Online Mendelian Inheritence in Man.

It is a database for cataloging human genes and genetic diseases. It was first created by Dr. Victor McKusick of Johns Hopkins

Question 16

What are the various databases that are used?

Answer 16

OMIM

ENCODE (Encyclopedia of genetic elements)

UCSC

Question 17

How was ENCODE developed? [know briefly]

Answer 17

2003: The human genome project was complete
2005: The human epigenome project aimed to identify, catalogue, and interpret genome-wide DNA methylation patterns of all genes in all major tissues
2006: International human epigenome project (IHEP) was developed
2007: ENCODE project
* Knowing this gives context to the purpose of the ENCODE project*

Question 18

What is the purpose of ENCODE?

Answer 18

ENCyclopedia Of Dna Elements

Began as a pilot project on 1% of the genome

In 2007 the effort was scaled to whole-genome assays followed by expansion to similar assays in mouse.

Project continues to create a comprehensive catalog of gene elements and functional elements in human and mouse genomes.

Question 19

How does ENCODE project get its catalog of gene elements and functional elements?

Answer 19

Measuring RNA expression levels

Identifying proteins that interact with RNA and DNA (eg. modified histones, transcription factors and RNA-binding proteins)

Measuring levels of DNA methylation and identifying regions of DNA hypersensitivity

Question 20

What causes genetic variation in populations?

Answer 20

New alleles introduced by mutation

Migration changes and population composition

Mating may be random or assortative and may involve
inbreeding or outbreeding

Recombination produces new combinations of alleles

Random fluctuation in reproductive rates may result in genetic drift in allele
frequencies

Differential reproduction by different genotypes may
result in natural selection

Question 21

What is population genetics?

Answer 21

Genetic variation within a population: Genetic composition

Comparison of populations

Processes that lead to changes in genetic composition

Question 22

What is mutation rate defined as?

Answer 22

Probability that a copy of an allele changes to another allelic form in one generation.

Question 23

How do mutations change with the number of generations?

Answer 23

Population homozygous to A with mutation to ‘a’ at a rate of 1/100000 will have ‘a’ at a rate of 0.00001. This process will repeat continuously with a steady decline.

This is not the full picture because it takes a huge number of generations to drop like that. Especially when actual mutation rate is much slower.

Question 24

What other processes act in addition to mutation to create more variation?

Answer 24

Migration

Selection

Non-random mating

Random events

Question 25

What are the important mating patterns?

Answer 25

Random mating

Non-random mating:

Assortative mating (+ve vs -ve)

Inbreeding (mating between relatives occurs more often than expected by chance)

Question 26

What are positive and negative assortative mating?

Answer 26

Mating with people that are similar to you = +ve

Mating with people that are different = -ve

Question 27

What is the result of non-random mating?

Answer 27

The increase in homozygosity

Question 28

What happens if there is inbreeding?

Answer 28

Affects all genes rather than just preference traits.

Causes departure from hardy weinberg frequencies

Leads to increase in proportion of homozygotes and decrease in proportion of heterozygotes in a population

Question 29

What does it mean for alleles to be identical by state?

Answer 29

2 alleles are alike in structure and function but do not have a common origin

Question 30

What does it mean for alleles to be identical by descent?

Answer 30

Alleles are alike due to being from the same ancestor several generations ago