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What Is the Genetic Basis of Complex Traits?

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What Is the Genetic Basis of Complex Traits? CH927 Quantitative Genomics What is the genetic basis of complex traits? One of the most enduring problems in evolution and molecular biology What is the genetic basis of complex traits? • Lecture 1 (Mon 9:30-10:30): markers, maps • Lecture 2 (Mon 11:00-12:00): QTL methods • Wet-bench practical (Mon 13:15-16:15): data for QTL mapping ** bus leaves to go to Warwick HRI at 12pm ** • Lecture 3 (Tues 9:30-10:30): Alternative methods: association mapping • Lecture 4 (Tues 10:45-11:45): eQTL mapping • Workshop (Tues 14:00-17:00): eQTL analysis using R-QTL Lecture objectives By the end of this lecture you should be able to explain: • Quantitative genetics: homozygotes, heterozygotes and inheritance • The basis and features of quantitative vs. qualitative traits • Why genetic markers are needed for QTL mapping • How genetic maps are created And know what you’ll be doing in this afternoon’s practical at Warwick HRI • Many sequenced genomes • Huge cost! • But still not easy to identify the right genes Some definitions in molecular genetics Genetics: the study of inheritance and its variations Gene: the segment of DNA involved in producing a protein Locus: a region of the genome, commonly a gene DNA promoter exon intron exon intron exon DNA Chromosome: A linear end-to-end arrangement of genes and other DNA, sometimes with associated protein and RNA Genome: the entire complement of genetic material in an organism Homozygosis vs. Heterozygosis Self pollination Cross pollination Plant A Plant B ♂ ♀ ♀ ♂ e.g. one pair of chromosomes pair is split Meiosis re-association (F1) Identical Different chromosomes chromosomes Identical genes Different genes homozygous heterozygous Also during meiosis: crossing over occurs Diploid: pair of chromosomes from cross- pollination Duplication of the chromosomes We can use this property to localise the parts of Crossing-over chromosomes involved in a trait Separation of chromosomes at end of meiosis Quantitative vs. Qualitative traits • Qualitative traits follow ‘Mendelian’ inheritance • Can predict the phenotype from the alleles carried e.g. A locus for eye colour with 2 alleles, B and b - four possible combinations: BB Bb bB bb • Dominant allele: same phenotypic character when heterozygous or homozygous (Brown eyes: Bb bB BB) • Recessive allele: phenotypic effect is expressed in homozyous state but masked in heterozygous (Blue eyes in bb only) Qualitative trait characteristics • For qualitative traits you can predict the phenotype from the alleles being carried • These traits are often encoded by single genes e.g. albinism Quantitative trait characteristics • ‘Infinitesimal model’: genetic variation in a trait due to a large number of loci, each of small effect • Many genotypes can produce the same phenotype • Quantitative traits often vary along a continuous gradient e.g. height, skin colour diseases such as cancer disorders such as epilepsy non-Mendelian inheritance What is the genetic basis of complex traits? • Complexity of these traits, esp. those involved in adaptation probably arises from segregation of alleles at many interacting loci = Quantitative Trait Loci (QTL) • QTL effects are sensitive to the environment • Combination of molecular genetics and statistical techniques are needed to identify where these QTLs are located Quantitative trait characteristics • No typical patterns of dominance and recessiveness • Locus contributions thought to be additive (assumed) = polygenic, or quantitative inheritance • This can be explained as Mendelian inheritance at many loci (n) • The coefficients of the binomial expansion of (a + b)2n will give the frequency of distribution of all n allele combinations • For a sufficiently high n, this binomial distribution will begin to be normal increasing disease threshold for disease to occur Lecture objectives By the end of this lecture you should be able to explain: • Quantitative genetics: homozygotes, heterozygotes and inheritance • The basis and features of quantitative vs. qualitative traits • Why genetic markers are needed for QTL mapping • How genetic maps are created Objectives of QTL analysis • The statistical study of the alleles that occur in a locus and the phenotypes (traits) that they produce • Methods developed in the 1980s, perform on inbred strains of any species 1. Score a population for (i) a trait, and (ii) distribution of genome markers 2. Associate occurence of a marker with the phenotype What do you need for QTL analysis? • (i) A large population of individuals that you can score for phenotypes and genotypes: Recombinant Inbred Lines (RILs) • (ii) A map of the genome to find out where you are (find out which chromosome the QTL is on) • (iii) Markers over the genome to pinpoint QTL location - features to distinguish sequence from different origins • (iv) A way to compare identify which markers from each parent have been inherited by the progeny A x B Parents = Homozygous F1 = Heterozygous at all loci crossing-over (recombination) F2 = x Heterozygous at some loci Many different individuals are obtained & separately x5 selfed to develop RILs F7 RILs = Homozygous at all loci & heterogeneous (i) A large population of mapping Recombinant Inbred Lines (ii) Markers to enable identification of which parental genome each part of the chromosomes of the progeny have come from parent A parent B parent A parent B • Visible phenotypes or molecular markers (DNA sequence differences) (iii) A map of the genome: anchor the markers Parent A Chr 1 Parent A Chr 2 Different chromosomes Molecular markers = features of the DNA sequence Markers differ between parents (natural variants) Parent A Parent B Chr 1 Chr 1 Different species variants single nucleotide polymorphisms GAATTC GATTTC (iv) You can distinguish these sequence differences using molecular techniques = molecular markers • Restriction enzymes e.g. EcoRI cut DNA only at a specific recognition sequence • Compare restriction patterns: Parent A Parent B ........GAATTC.......GAATTC.......GAATTC....... ........GAATTC.......GATTTC.......GAATTC....... ........GAATTC.......GAATTC.......GAATTC....... ........GAATTC.......GATTTC.......GAATTC....... First generation (F1) Second generation (F2) from selfing F1: There are many types of molecular markers • Restriction Fragment Length Polymorphisms (RFLPs) • Simple Sequence Length Polymorphisms (SSLPs) • Cleaved Amplified Polymorphic Sequences (CAPS) • Microsatellites (repeated sequences of 1-6 bases) • Essentially, all of these are methods with which to detect sequence differences that have occured between two variants of a species • They mostly differentiate single nucleotide polymorphisms (snps) Lecture objectives By the end of this lecture you should be able to explain: • Quantitative genetics: homozygotes, heterozygotes and inheritance • The basis and features of quantitative vs. qualitative traits • Why genetic markers are needed for QTL mapping • How genetic maps are created Need to know the linkage order: making a genetic map There are two types of maps: • Physical map: lays out the sequence information and annotates it: promoters, genes etc. a A • Linkage map: order of genetic markers and relative distances from each other - plus how much meiotic recombination (crossing over) there is between homologous chromosomes carrying alternative alleles (genetic markers) B b Genetic linkage is related to recombination frequency • Are loci A and B linked (on same chromosome) or unlinked (different chromosomes)? a A a A a A B b a B b A B b B b More recombination Little recombination so Rf = high ( <0.5 ) so Rf = small = weak linkage = tight linkage Some recombination Rf = 0.5 (50%) so Rf = medium = no linkage aB, Ab, ab, and AB = quantifiable linkage Only aB and Ab in similar proportions aB, Ab, ab, and AB Rf = recombination More aB, Ab than ab, AB in equal proportions frequency a A Map distances and genetic linkage B b • Recombination frequency of 0.01 (1%) = a genetic map unit of 1 cM • Recombination events occur randomly, once or twice per chromosome • A linkage map is made by characterising the recombination events that have taken place in a cross between two parental genotypes ** Every individual cross will have an individual linkage map ** • To make a map you need to score many markers in many individuals • Assumes that linkage is the only cause of non-independence between markers and that segregation is Mendelian a A Determining map order B b • Likelihood ODds ratio: likelihood of the observed linkage • The higher the LOD score, the more closely linked the markers are • Data on the presence/absence of 100s of markers in (F7) progeny population • Then you can use statistics to work out the marker order • Traditionally done by hand using e.g. the Chi-squared statistic to test for goodness of fit for the observed segregation ratios between markers • With even just 10 marker scores, this means looking at many combinations: 1 2 3 4 5 6... 1 3 2 4 5 6... 1 3 4 2 5 6... and so on... = (10 x 9 x 7 x 6 x 5 x 4 x 3 x 2 x 1)/2 = 1,814,400 possible orders!! • That’s a lot of Chi-squared tests! • So we use mapping software e.g. Mapmaker, JoinMap Determining map order • Recombination fraction = n recombinant gametes total • Haldane mapping function adjusts map distance to account A a for double crossovers that go undetected B b • Map distance ≈ (RAB + RAC - 2RABRBC) x 100 cM C c • 2RABRAC is negligible for <10cM • Kosambi mapping function also adjusts for crossover interference i.e. a crossover reduces the probability of a second crossover nearby Linkage groups are the basis of genetic maps These should theoretically correspond to chromosomes, but if... • Chromosomes very long • Recombination frequency very high • Mapping populations are not large enough ...one chromosome can statistically “break” into several linkage groups • Also, centromeres and heterochromatin have supressed recombination A genetic linkage map for broccoli 1 2 3 4 5 6 7 8 9 map units cM • Recombination frequency of 0.01 (1%) = a genetic map unit of 1 cM.
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