CMSC423: Bioinformatic Algorithms, Databases and ToolsSome GeneticsCMSC423 Fall 2009 2Reading assignment●Chapter 13CMSC423 Fall 2009 3Gene association studies●Goal: identify genes/markers associated with disease●Example: BRCA1 – associated with risk of breast cancer●Lots of hype on the news recently: companies promise to “sequence” your genome and tell you:●likely ancestry●risk for disease●Examples: ●www.23andme.com●www.decodeme.com●and many othersCMSC423 Fall 2009 4First...definitions●Genotype – genetic composition of our genome●Phenotype – observable consequence of genotype – e.g. skin/hair color, IQ, disease state, etc.●We have two copies of each chromosome (homologous chromosomes), each received from one of the parents●Each gene can, thus, have two forms (alleles), e.g. A1/A2●Each gene may be associated with a phenotype●Dominant gene – phenotype of A1/A2 is the same as phenotype of A1/A1●Recessive gene - otherwiseCMSC423 Fall 2009 5More definitions●Genotype A/A is called homozygous (both chromosomes have the same allele)●Genotype A/B is called heterozygous (mother and father's chromosomes disagree)●Notes:●phenotypes not necessarily directly correlated with a single gene – polygenic traits●probability gene correlates with a phenotype – penetrance●link between genotype and phenotype can be qualitative (gene “form” matters) or quantitative (gene dosage matters)CMSC423 Fall 2009 6Technology – what we measure?●Definition of allele/genotype depends on what we can measure – constantly changing●We are looking for things that differ within a population – polymorphic markers:●Restriction fragment length polymorphism (RFLP)– measures presence/absence of particular sites in the genome●Variable number tandem repeats (VNTR) – specific repeat elements that occur in different copy numbers ●Single-nucleotide polymorphisms (SNPs) – single letter differences between chromosomes (>500,000 characterized)●Copy number variants (CNV) – genomic regions whose copy number differs between individualsCMSC423 Fall 2009 7Allele frequencies●Population genetics questions:●what alleles exist in a certain population?●what is the relative abundance of the alleles?●how “diverse” is a population?●Given a locus (gene or genomic region), assume there are K possible alleles in a population and allele j occurs with frequency pj●How “uniform” is the locus in the population? Likelihood two random individuals have same allelehomzygosity F =∑i=1Kpi2CMSC423 Fall 2009 8Allele frequencies...●Usually we focus on the differences:●Interesting tidbit – most variation occurs within populations rather than between, e.g. two Africans are more different from each other than the average African is from the average Chinese (see book for details)● However, allele frequencies can be used to infer population membership for an individualheterzygosity H = 1− F = 1−∑i=1Kpi2CMSC423 Fall 2009 9Who am I?●My alleles are A1, B2, C1, D3 (assume homozygous for clarity)●Am I European or Asian?●Need to know: pA1Europe, pB2Europe, pC1Europe, pD3EuropepA1Asia, pB2Asia, pC1Asia, pD3Asia●p(me, European) = (pA1Europe )2X (pB2Europe )2X (pC1Europe )2X (pD3Europe)2●similarly for p(me, Asian)●if p(me, European) > p(me, Asian) I can infer that I have European ancestryCMSC423 Fall 2009 10Who am I?●Inferring ancestry as described is overly-simplistic●Can do more fancy statistics●However: any statistical approach is error prone – answer is associated with level of confidence, i.e. probability answer is wrong (remember P-values?)●Beware of anyone who claims to infer your ancestry from genotype●Beware of anyone who claims to infer disease susceptibility from genotype - need genetic/risk counselors not companies providing information for “entertainment purposes”CMSC423 Fall 2009 11Recombination●Genetic change not only caused by mutations●Recombination – DNA “jumps” between homologous chromosomes due to cross-over eventsA1 B1 C1 D1 A1 B1 C1 D1A2 B2 C2 D2 A2 B2 C2 D2A1 B1 C2 D2A2 B2 C1 D1A1 B1 C2 D1A2 B2 C1 D2CMSC423 Fall 2009 12Association studies●The set of alleles on a same chromosome – haplotype●If a particular allele of a gene is always associated with a phenotype (disease) – is this gene causing the disease?●Most likely – gene is associated/nearby with the gene causing the disease (their alleles always appear on the same haplotype)●Due to recombination a set of original haplotypes rapidly becomes broken apart●How likely is it that two alleles remain on the same haplotype (are linked) during evolution?CMSC423 Fall 2009 13Linkage analysis●Preservation of linkage depends on distance between the genes and rate of recombination●Given two genes (A, B) – how can we estimate whether recombination occurred between them?●How likely is it that A1 and B1 are both on the same haplotype by chance?p(A1)p(B1)●How different is this from the observed ratios? - Linkage DesequilibriumD = p(A1B1) – p(A1)p(B1)D = p(A2B2) – p(A2)p(B2) D = p(A1B1)p(A2B2) - p(A1B2)p(A2B1)CMSC423 Fall 2009 14Linkage analysis●Linkage desequilibrium usually measured as ratio to maximum possible desequilibrium - D/DmaxDmax = min(p(A2)p(B1), p(A1)p(B2)) if D > 0Dmax = min(p(A1)p(B1), p(A2)p(B2)) if D < 0●Another measure – Pearson's correlation coefficientr2 = D2/(p(A1)p(A2)p(B1)p(B2)CMSC423 Fall 2009 15Additional resources●www.hapmap.org●www.1000genomes.org●www.personalgenomes.org●http://www.ncbi.nlm.nih.gov/sites/entrez?db=omimCMSC423 Fall 2009 16Questions●Prove the equalities on slide 13 (D = ...)●Derive the formula for Dmax on slide 14 (problem 3.5 in