QTs IIIb: “miraculous” and “missing” heritability (1) Selection should “use up” VA, by fixing the favorable alleles. But it doesn’t (at least in many cases). The Illinois Long-term Selection Experiment (1896-2015, and continuing*), has artificially selected corn for high and low oil and protein content.

Anth/Biol 5221, 21 April 2020

The “down” lines were abandoned in the late 20th century…

… 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?

*http://mooselab.cropsci.illinois.edu/longterm.html

(2) For many traits with high heritabilities, only small fractions of VA can be accounted for by the mappable quantitative trait loci (QTL). Human height is one of many examples. More than 1000 QTL can be identified by linkage disequilibrium with SNP marker loci.

But these 1000 QT loci, together, explain only 10-15% of the observed heritability!

Where’s the rest of it?

h2 = 0.82

h2 = 0.98

Utah Genetic Reference Project

Logic of QTL mapping in a study of hybrids between Mimulus cardinalis and Mimulus lewisii.

(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 Wikipedia article “Schizophrenia” (ca. 2017)

“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.”

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.

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)?

Ripke et al. Nat. Genet. 45, 1150-1159 (2013)

QTL mapping suggests that there are modest numbers of genes with major effects, on many chromosomes.

And some of these are plausible “candidate” genes

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

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?

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?

This was proposed 53 years ago by

Irving Gottesman. (Gottesman & Shields, PNAS 58,

199-205 (1967)

American Journal of Human Genetics 35, 1161-1178 (1983)

One possibility: frequent copy-

number mutations

New deletion of ~2 Mb

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 review of this idea, emphasizing evolution more than medicine.)

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, 894-994 (2013)

Recent evidence for many alleles of small effect, II

Ripke et al.,Nat. Genet. 45, 1150-1159 (2013)

“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.” Rheumatoid Arthritis

Myocardial infarction

Type 2 diabetes

Combined analysis of two large studies

Marouli et al. (2017) Nature 542: 186-190

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.

Minor allele frequency

Effe

ct s

ize

If more loci contribute to VA, there is more scope for evolution.

6 loci

p = 0.5

p = 0.75

p = 0.95

x min x max

25 loci

p = 0.5

p = 0.75

p = 0.95

x min x max

p = 0.5

p = 0.75

p = 0.95

100 loci

Mean up 3.1 s.d.

Mean up 6.3 s.d.

Mean up 12.9 s.d.

Summary Large amounts of heritable variation could be caused by very small contributions to VA from many different loci. Such “small-effect” alleles may help to explain why VA 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.”