Genetic Variation II Flashcards
What was the focus of the HapMap project?
To ultimately produce a fine scale genetic map which would serve as a common resource for all biomedical researchers.
Which populations did the HapMap project look at?
4 populations:
CEPH (Europe)
Yoruban (Africa)
Japanese/Chinese (Asian)
What was phase I of the HapMap project?
One million common SNPs (every 5 kb across the genome) were genotyped in 269 DNA samples from 4 populations
What was phase II of the HapMap project?
An additional 4.6million SNPs are genotyped
What is investigated in the 1000 genomes project?
1092 genomes are sequences including 14 populations
Whole genome was sequenced (Low coverage: 2 - 6x) and the exome (deep coverage 50 - 100x)
What is the most recent phase of the 1000 genomes project?
Phase 3 which investigates 2535 individuals and 26 populations with a high coverage of both exome and whole-genome data.
Does genetic variation have harmful consequences on people?
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.
Why is it hard to know which genes are functionally important?
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
What are the 2 extremes with regard to mutation and functional change?
Virtually all amino acids can be replaced while maintaining original function.
OR
Single mutation may give rise to completely new function
What must be considered when more than 1 mutation is required for new function?
The order of mutational events.
What does this “5162 G-A” mutation nomenclature mean?
5162 = Base position
G = original base
A = replacement base
What does this “197delAG” mutation nomenclature mean?
197 = position
del = deletion
AG = bases being deleted
What does this “R197G” mutation nomenclature mean?
R = original amino acid
197 = amino acid position
G = replacement
What is a conservative mutation?
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.
What is OMIM?
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
What are the various databases that are used?
OMIM
ENCODE (Encyclopedia of genetic elements)
UCSC
How was ENCODE developed? [know briefly]
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*
What is the purpose of ENCODE?
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.
How does ENCODE project get its catalog of gene elements and functional elements?
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
What causes genetic variation in populations?
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
What is population genetics?
Genetic variation within a population: Genetic composition
Comparison of populations
Processes that lead to changes in genetic composition
What is mutation rate defined as?
Probability that a copy of an allele changes to another allelic form in one generation.
How do mutations change with the number of generations?
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.
What other processes act in addition to mutation to create more variation?
Migration
Selection
Non-random mating
Random events
What are the important mating patterns?
Random mating
Non-random mating:
Assortative mating (+ve vs -ve)
Inbreeding (mating between relatives occurs more often than expected by chance)
What are positive and negative assortative mating?
Mating with people that are similar to you = +ve
Mating with people that are different = -ve
What is the result of non-random mating?
The increase in homozygosity
What happens if there is inbreeding?
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
What does it mean for alleles to be identical by state?
2 alleles are alike in structure and function but do not have a common origin
What does it mean for alleles to be identical by descent?
Alleles are alike due to being from the same ancestor several generations ago
