QTs IV: miraculous and missing heritability

Transcription

1 QTs IV: miraculous and missing heritability (1) Selection should use up V A, by fixing the favorable alleles. But it doesn t (at least in many cases). The Illinois Long-term Selection Experiment ( , and continuing*), has artificially selected corn for high and low oil and protein content. but the up lines are still increasing at a nearly constant rate! Both are now up by more than 10 s.d.! How is this possible? The down lines were abandoned in the late 20 th century * Anth/Biol 5221, 5 December 2018

2 (2) For many traits with high heritabilities, only small fractions of V A can be accounted for by the mappable quantitative trait loci (QTL). Human height is one of many examples. More than 700 QTL can be identified by linkage disequilibrium with SNP marker loci. h 2 = 0.98 Logic of QTL mapping in a study of hybrids between Mimulus cardinalis and Mimulus lewisii. h 2 = 0.82 But these 700 QT loci, together, explain only around 10% of the observed heritability! Where s the rest of it? Utah Genetic Reference Project

3 Why is schizophrenia so common? It afflicts more than 1 in 200 people. It is highly heritable. And it dramatically lowers fitness. There is little doubt about the existence of a fecundity deficit in schizophrenia. Affected individuals have fewer children than the population as a whole. This reduction is of the order of 70% in males and 30% in females. The central genetic paradox of schizophrenia is why, if the disease is associated with a biological disadvantage, is this variation not selected out? To balance such a significant disadvantage, a substantial and universal advantage must exist. Thus far, all theories of a putative advantage have been disproved or remain unsubstantiated. From the Wikipedia article Schizophrenia Data from a PET [positron emission tomography] study suggest that the less the frontal lobes are activated (red) during a working memory task, the greater the increase in abnormal dopamine activity in the striatum (green), thought to be related to the neurocognitive deficits in schizophrenia.

4 And the heritabilities are amazing! (Thank you, twins!) Note that several conditions considered distinct diseases by mental-health professionals are strongly correlated genetically (MZ twins are diagnosed with different ones of them much more often than are DZ twins). This has fueled debate about the reality of the distinctions.

5 What is the genetic architecture of these susceptibilities? Mutations in a few genes with large effects? If so, which genes are they? Or is it polymorphisms at many loci, each making a small contribution? And in either case, what kinds of mutations are involved? Unconditionally deleterious? Or good-news/bad-news tradeoffs? Amino-acid and nucleotide substitutions? Or duplications and deletions (copy-number variation)?

6 QTL mapping suggests that there are modest numbers of genes with major effects, on many chromosomes. Ripke et al. Nat. Genet. 45, (2013)

7 And some of these are plausible candidate genes

8 Many play well established roles in neurotransmission, in or near synapses.

9 But again there s this large and familiar problem: The major-effect genes explain just a fraction of the heritability! Where s the rest of it? Could susceptibility be a highly polygenic quantitative trait? This was proposed 50 years ago by Irving Gottesman. (Gottesman & Shields, PNAS 58, (1967) But if that s the case, where is all this heritable variation hiding? And why is there so much of it, given that selection against schizophrenia is very strong? American Journal of Human Genetics 35, (1983)

10 One possibility: frequent copynumber mutations New deletion of ~2 Mb

11 But there are other possibilities, for example: (1) very many genes with alleles of very small effect (2) very many genes with alleles of infrequent effect (low penetrance) (3) complex genetic interactions (epistasis, dominance, etc.) (4) epigenetics (imprinting or other environmental pseudo-heritability ) However, not all of these can easily explain the very high levels of heritability seen in the twin studies and other direct pedigree analyses. Nor can they all easily explain why selection experiments do not run out of additive variance, even when mean values have been changed by many standard deviations. But possibility #1 (very many loci, each with very small effects) can explain all of the observations, at least in principle. (See Rockman [2012] on the course web site for an entertaining recent review of this idea, emphasizing evolution more than medicine.)

12 Recent evidence for many alleles of small effect, I SNP heritability studies estimate the total variance in liability explained by SNPs, which are used to estimate the pairwise genetic relationships of cases and controls. Genetic variation is indicated to the degree that case-case and control-control pairs are, on average, more similar across the genome than case-control pairs. Cross-Disorder Group of the Psychiatric Genomics Consortium Nat. Genet. 45, (2013)

13 Recent evidence for many alleles of small effect, II Myocardial infarction Rheumatoid Arthritis Combined analysis of two large studies Type 2 diabetes We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300 10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Ripke et al.,nat. Genet. 45, (2013)

14 Recent evidence for many alleles of small effect, III Alleles with relatively large effects on height can be found. But all are rare! Thus they explain only a small fraction of the variance. Effect size Minor allele frequency Marouli et al. (2017) Nature 542:

15 If more loci contribute to V A, there is more scope for evolution. x min x max x min x max p = loci p = 0.75 p = 0.95 Mean up 3.1 s.d. p = 0.5 p = loci p = loci p = 0.75 p = 0.95 Mean up 6.3 s.d. p = 0.95 Mean up 12.9 s.d.

16 Summary Large amounts of heritable variation could be caused by very small contributions to V A from many different loci. Such small-effect alleles may help to explain why V A is not quickly depleted by strong, continued selection (the miraculous heritability). They may also account for the variation that cannot be associated with markers, even in enormous QTL studies (the missing heritability). Deleterious small-effect mutations could drift upward at many loci, or hitchhike with closely linked adaptive mutations, because selection against the disfavored allele at each of the many loci would be weak. Thus our surprising susceptibility to schizophrenia and related disorders might be, in part, a consequence of our species history of small population size, or a side effect of recent rapid mental evolution. If so, is Wikipedia s assertion necessarily correct? The central genetic paradox of schizophrenia is why, if the disease is associated with a biological disadvantage, is this variation not selected out? To balance such a significant disadvantage, a substantial and universal advantage must exist.