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Gene$c Varia$on and Gene$c Diversity 02-­‐223 How to Analyze Your Own Genome Fall 2013 Terminology •  Allele: different forms of gene@c varia@ons at a given gene or gene@c locus –  Locus 1 has two alleles, A and T, and Locus 2 has two alleles, C and G •  Genotype: specific allelic make-­‐up of an individual’s genome –  Individual 1 has genotype AA at Locus 1 and genotype CG at Locus 2 •  Heterozygous/Homozygous –  Locus 1 of Individual 1 is homozygous, and Locus 2 is heterozygous Individual 1 C A G Locus 2 A Locus 1 C Individual 2 A T Locus 1 C Locus 2 Single Nucleo$de Polymorphisms (SNPs) Advantages of SNPs in Popula$on Gene$cs Studies • 
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Abundance: high frequency on the genome Posi@on: throughout the genome –  coding region, intron region, promoter site Ease of genotyping (high-­‐throughput genotyping) Less mutable than other forms of polymorphisms SNPs account for around 90% of human genomic varia@on About 10 million SNPs exist in human popula@ons Most SNPs are outside of the protein coding regions 1 SNP every 600 base pairs More than 5 million common SNPs each with frequency 10-­‐50% account for the bulk of human DNA sequence difference It is es@mated that ~60,000 SNPs occur within exons; 85% of exons are within 5 kb of the nearest SNP Account for most of the genetic diversity among different (normal) individual, e.g. drug
response, disease susceptibility"
However, only two alleles at each locus, less informa@ve than microsatellites. (Use haplotypes!) Working with SNP Data in Prac$ce •  At each locus, SNPs are represented as 0 or 1. –  A/T/C/G lecers are converted to 0 or 1 for minor/major alleles –  Genotypes at each locus of each individual are coded as •  0 : minor allele homozygous •  1: heterozygous •  2: major allele homozygous •  Given genotype data for N individuals •  For each locus, we can define minor allele frequency as follows: (Minor allele frequency) = (the number of minor alleles in the popula@on)/(total number of alleles in the popula@on) •  Typically, SNPs with a very low minor allele frequency are discarded, since they don’t contain sufficient informa@on about gene@c diversity The Effects of Single Nucleo$de Muta$ons •  Muta@ons in the protein coding regions –  Nonsynonymous muta@ons •  Missense muta@ons change the protein sequence –  CAC in RNA (or DNA) codes for amino acid his, but if A is mutated to U (CUC), it codes for amino acid leu •  Nonsense muta@ons truncate the protein –  UGG codes for amino acid trp, but if G is mutated to A (UAG), it becomes a stop codon. –  Synonymous muta@ons do not change amino acids •  Both CAC and CAU result in amio acid his •  However, such muta@ons could affect splice sites •  Muta@ons in the regulatory (non-­‐coding) regions –  We have very licle understanding of the regulatory regions and muta@ons in them Gene$c Polymorphisms •  Inser@on/dele@on of a sec@on of DNA – 
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Minisatellites: repeated base pacerns (several hundred base pairs) Microsatellites: 2-­‐4 nucleo@des repeated Presence or absence of Alu segments Many alleles, very informa@ve because of the high heterozygosity (the chance that a randomly selected person will be heterozygous) Gene$c Polymorphisms •  Structural variants –  inser@ons/dele@ons, duplica@ons, copy number varia@ons Gene$c Polymorphisms •  Copy Number Varia@on –  DNA segment whose numbers differ in different genomes •  Kilobases to megabases in size –  Usually two copies of all autosomal regions, one per chromosome –  Varia@on due to dele@on or duplica@on Gene$c Polymorphisms •  Copy Number Varia@ons + SNPs Detec$ng Gene$c Polymorphisms from Shotgun Sequencing Gene$c Variant Frequencies from 1000 Genome Pilot Project Frequency of SNPs greater than that of any other type of polymorphism Gene$c Markers •  Gene@c markers –  DNA sequence with a known physical loca@on on a chromosome –  An iden@fiable segment of DNA (e.g., SNPs, microsatellites) with enough varia@on between individuals that its inheritance and co-­‐
inheritance with alleles of a given gene can be traced –  Gene@c markers can be used to refer to a par@cular loca@on in genomes or in a gene@c map. hcp://www.genome.gov/glossary/index.cfm?id=86 Check out the “Listen” voice recording of Dr. Hurle’s explana@on of gene@c markers Summry •  Alleles and genotypes •  Different types of gene@c polymorphisms –  Single nucleo@de polymorphisms (SNPs) –  Structural variants •  Inser@ons, dele@ons, copy number varia@ons etc. –  SNPs are the most abundant polymorphisms and are oqen used as gene@c markers