How Recessive is a Recessive Mutation?

Many relationships exist between mutation, copy number, and phenotype.

The traditional setup of Mendelian genetics is that an allele of a gene is either recessive or dominant. Blue eyes are recessive to brown eyes, for the simple reason that blue arises from the absence of an enzyme, due to a loss of function mutation. So having some of that enzyme, from even one "brown" copy of that gene, is dominant over the defective "blue" copy. You need two "blue" alleles to have blue eyes. This could be generalized to most genes, especially essential genes, where lacking both copies is lethal, while having one working copy will get you through, and cover for a defective copy. Most gene mutations are, by this model, recessive. 

But most loci and mutations implicated in disease don't really work like that. Some recent papers delved into the genetics of such mutations, and observed that their recessiveness was all over the map, a spectrum, really, of effects from fully recessive to dominant, with most in the middle ground. This is informative for clinical genetics, but also for evolutionary studies, suggesting that evolution is not, after all, blind to the majority of mutations, which are mostly deleterious, exist most of the time in the haploid (one-copy) state, and would be wholly recessive by the usual assumption.

The first paper describes a large study over the Finnish population, which benefited from several advantages. Finns have a good health system with thorough records which are housed in a national biobank. The study used 177,000 health records and 83,000 variants in coding regions of genes collected from sequencing studies. Second, the Finnish population is relatively small and has experienced bottlenecks from smaller founding populations, which amplifies the prevalence of variants that those founders had. That allows those variants to rise to higher rates of appearance, especially in the homozygous state, which generally causes more noticeable disease phenotypes. Both the detectability and the statistics were powered by this higher incidence of some deleterious mutations (while others, naturally, would have been more rare than the world-wide average, or absent altogether).

Thirdly, the authors emphasize that they searched for various levels of recessive effect, which is contrary to the usual practice of just assuming a linear effect. A linear model says that one copy of a mutation has half the effect of two copies- which is true sometimes, but not most of the time, especially in more typical cases of recessive effect where one copy has a good deal less effect, if not zero. Returning to eye color, if one looks in detail, there are many shades of eyes, even of blue eyes, so it is evident that the alleles that affect eye color are various, and express to different degrees (have various penetrance, in the parlance). While complete recessiveness happens frequently, it is not the most common case, since we generally do not routinely express excess amounts of proteins from our genes, making loss of one copy noticeable most of the time, to some degree. This is why the lack of a whole chromosome, or an excess of a whole chromosome, has generally devastating consequences. Trisomies in only three chromosomes are viable (that is, not lethal), and confer various severe syndromes.

A population proportion plot vs age of disease diagnosis for three different diseases and an associated genetic variant. In blue is the normal ("wild-type") case, in yellow is the heterozygote, and in red the homozygote with two variant alleles. For "b", the total lack of XPA causes skin cancer with juvenile onset, and the homozygotic case is not shown. The Finnish data allowed detection of rather small recessive effects from variations that are common in that population. For instanace, "a" shows the barely discernable advancement of age of diagnosis for a disease (hearing loss) that in the homozygotic state is universal by age 10, caused by mutations in GJB2.

The second paper looked more directly at the fitness cost of variations over large populations, in the heterozygous state. They looked at loss-of-function (LOF) mutations of over 17,000 genes, studying their rate of appearance and loss from human populations, as well as in pedigrees. These rates were turned, by a modeling system, into fitness costs, which are stated in percentage terms, vs wild type. A fitness cost of 1% is pretty mild, (though highly significant over longer evolutionary time), while a fitness cost of 10% is quite severe, and one of 100% is immediately lethal and would never be observed in the population. For example, a mutation that is seen rarely, and in pedigrees only persists for a couple of generations, implies a fitness cost of over 10%.

They come up with a parameter "hs", which is the fitness cost "s" of losing both copies of a gene, multiplied by "h", a measure of the dominance of the mutation in a single copy.

In these graphs, human genes are stacked up in the Y axis sorted by their computed "hs" fitness cost in the heterozygous state. Error bars are in blue, showing that this is naturally a rather error-prone exercise of estimation. But what is significant is that most genes are somewhere on the spectrum, with very few having negligible effects, (bottom), and many having highly significant effects (top). Genes on the X chromosome are naturally skewed to much higher significance when mutated, since in males there is no other copy, and even in females, one X chromosome is (randomly) inactivated to provide dosage compensation- that is, to match the male dosage of production of X genes- which results in much higher penetrance for females as well.

So the bottom line is that while diploidy helps to hide alot of variation in sexual organisms, and in humans in particular, it does not hide it completely. We are each estimated to receive, at birth, about 70 new mutations, of which 1/1000 are the kind of total loss of gene function studied here. This work then estimates that 20% of those mutations have a severe fitness effect of >10%, meaning that about one in seventy zygotes carry such a new mutation, not counting what it has inherited from its parents, and will suffer ill effects immediately, even though it has a wild-type copy of that gene as well.

Humans, as other organisms, have a large mutational load that is constantly under surveillance by natural selection. The fact that severe mutations routinely still have significant effects in the heterozygous state is both good and bad news. Good in the sense that natural selection has more to work with and can gradually whittle down on their frequency without necessarily waiting for the chance of two meeting in an unfortunate homozygous state. But bad in the sense that it adds to our overall phenotypic variation and health difficulties a whole new set of deficiencies that, while individually and typically minor, are also legion.

• Psychological projection, to the max.
• And another murder.
• Next up, book burnings.
• Medicare advantage is a corrupt disaster.
• Corporate health insurance says no.