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MIT HST 950J - Population Genetics in the Post-Genomic Era

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Population Genetics in the Post-Genomic Era Marco F. Ramoni Children’s Hospital Informatics Program Harvard Medical School HST 950 (2003) Harvard-MIT Division of Health Sciences and TechnologyHST.950J: Medical ComputingPeter Szolovits, PhD Isaac Kohane, MD, PhD Lucila Ohno-Machado, MD, PhDIntroduction •On February 12, 2001 the Human Genome Project announces the completion of a first draft of the human genome. •Among the items on the agenda of the announcement, a statement figures prominently: A SNP map promises to revolutionize both mapping diseases and tracing human history. •SNP are Single Nucleotide Polymorphisms, subtle variations of the human genome across individuals. •You can take this sentence as the announcement of a new era for population genetics.Outline Background 80s revolution and HGP Genetic Polymorphisms Their nature Types of polymorphisms Foundations Terminology Hardy Weinberg Law Types of inheritance Complex Traits Definition Factors of Complexity Study and Experiment Design Case Control Studies Pedigree Studies Analysis Methods Association Studies Linkage Studies Allele-sharing Studies QTL Mapping The New Ways Haplotypes HapMap htSNPsBackground Intuition: We can find the genetic bases of observable characters (like diseases) without knowing how the actual coding works. Origins: Sturtevant (1913) finds traits-causing genes. Early History: Genetic maps of plants and insects. Outcast: Ernst Mayr called it ¡°Beans bag genetics¡±. Reasons: No markers to identify coding regions. Markers: Botstein (1977) showed that naturally occurring DNA already contains markers identifying regions of the genome: polymorphisms.Central Dogma of Molecular Biology DNA RNA MRNA Proteins Traits Diseases Physiology Metabolism Drug ResistanceThe 80s Revolution and the HGP •The intuition that polymorphisms could be used as markers sparkled the revolution. •Mendelian (single gene) diseases: Autosomal dominant (Huntington). Autosomal recessive (C Fibrosis). X-linked dominant (Rett). X-linked recessive (Lesch-Nyhan). •Today, over 400 single-gene diseases have been identified. •This is the promise of the HGP.Terminology Allele: A sequence of DNA bases. Locus: Physical location of an allele on a chromosome. Linkage: Proximity of two alleles on a chromosome. Marker: An allele of known position on a chromosome. Distance: Number of base-pairs between two alleles. centiMorgan: Probabilistic distance of two alleles. Phenotype: An outward, observable character (trait). Genotype: The internally coded, inheritable information. Penetrance: No. with phenotype / No. with allele.Distances •Physical distances between alleles are base-pairs. But the recombination frequency is not constant. •Segregation (Mendel's first law): Allele pairs separate during gamete formation and randomly reform pairs. •A useful measure of distance is based on the probability of recombination: the Morgan. •A distance of 1 centiMorgan (cM) between two loci means that they have 1% chances of being separated by recombination. •A genetic distance of 1 cM is roughly equal to a physical distance of 1 million base pairs (1Mb).More Terminology Physical maps: Maps in base-pairs. Human autosomal physical map: 3000Mb (bases). Linkage maps: Maps in centiMorgan. Human Male Map Length: 2851cM. Human Female Map Length: 4296cM. Correspondence between maps: Male cM ~ 1.05 Mb; Female cM ~ 0.88Mb. Cosegregation: Alleles (or traits) transmitted together.Hemophilia, a Sex Linked Recessive •Hemophilia is a X-linked recessive disease, that is fatal for women. •X-linked means that the allele (DNA code which carries the disease) is on the X-chromosome. •A woman (XX) can be carrier or non-carrier: if x=allele with disease, then xX=carrier; xx=dies; XX=non carrier. •A male (YX) can be affected or not affected: (xY= affected; XY=not affected).Hemophilia: A Royal DiseaseGenetic Markers One of the most celebrated findings of the human genome project is that humans share most DNA. Still, there are subtle variations: Simple Sequence Repeats (SSR): Stretches of 1 to 6 nucleotide repeated in tandem. Microsatellite: Short tandem repeat (e.g. GATA) varying in number between individuals. Single nucleotide polymorphism (SNP): Single base variation with at least 1% incidence in population.Single Nucleotide Polymorphisms Variations of a single base between individuals: ... ATGCGATCGATACTCGATAACTCCCGA ... ... ATGCGATCGATACGCGATAACTCCCGA ... A SNP must occur in at least 1% of the population. SNPs are the most common type of variations. Differently to microsatellites or RTLPs, SNPs may occur in coding regions: cSNP: SNP occurring in a coding region. rSNP: SNP occurring in a regulatory region. sSNP: Coding SNP with no change on amino acid.Evolutionary Pressure •Kreitman (1983) sequenced the first 11 alleles from nature: alcohol dehydrogenase locus in Drosophila. •11 coding regions / 14 sites have alternative bases. •13 variations are silent: ie do not change amino acid. •With a random base change, we have 75% chances of changing the amino acid (i.e. creating a cSNP). •Why this disparity? •Drosophilae and larvae are found in fermenting fruits. •Alcohol dehydrogenase is important in detoxification. •A radical change in protein is a killer.Hardy-Weinberg Law Hardy-Weinberg Law (1908): Dictates the proportion of major (p), minor alleles (q) in equilibrium. p2 + 2pq + q2 = 1. Equilibrium: Hermaphroditic population gets equilibrium in one generation, a sexual population in two. Example: How many Caucasian carriers of C. fibrosis? Affected Caucasians (q2) = 1/2,500. Affected Alleles (q)= 1/50 = 0.02. Non Affected Alleles (p) = (1 - 0.02) = 0.98. Heterozygous (2pq) = 2(0.98 ¡Á 0.02) = 0.04= 1/25.Assumptions Random mating: Mating independent of allele. Inbreeding: Mating within pedigree; Associative mating: Selective of alleles (humans). Infinite population: Sensible with 6 billions people. Drift: Allele distributions depend on individuals offspring. Locality: Individuals mate locally; Small populations: Variations vanish or reach 100%. Mutations contrast drift by introducing variations. Heresy: This picture of evolution as equilibrium between drift and mutation does not include selection!Natural Selection Example: p=0.6 and q=0.4. Fitness (w): AA=Aa=1, aa=0.8. Selection: s = 1-w = 0.2: δp = Spq2 (0.2)(0.6)(0.4)2 0.019 = = = 0.02 1-sq2 1-(0.2)(0.4)2 0.968 Selection: Effect on the 1st generation is A=0.62


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