Pleiotropy is 100 years old

This year, the term pleiotropy was defined 100 years ago, and Frank Stearns, graduate student at the University of Maryland biology graduate program has written a perspective in Genetics, which I highly recommend.

Looking around umd.edu, I found that Stearn's research topic is "mutations in adaptive landscapes", which explains his interest in pleiotropy. I have the same interest for the same reason (see preprints here and here).

ABSTRACT

Pleiotropy is defined as the phenomenon in which a single locus affects two or more distinct phenotypic traits. The term was formally introduced into the literature by the German geneticist Ludwig Plate in 1910, 100 years ago. Pleiotropy has had an important influence on the fields of physiological and medical genetics as well as on evolutionary biology. Different approaches to the study of pleiotropy have led to incongruence in the way that it is perceived and discussed among researchers in these fields. Furthermore, our understanding of the term has changed quite a bit since 1910, particularly in light of modern molecular data. This review traces the history of the term "pleiotropy" and reevaluates its current place in the field of genetics.

Apparently this Ludwig Plate was a nazi and a misogynist. Sighs. Onward, upward.

Pleiotropy can be caused by one gene making two or more different proteins (alternative splicing) which then affect different traits, or by a single protein affecting multiple traits. The former used to be termed "genuine" pleiotropy, and the latter "spurious" pleiotropy. I'm not so hot on these terms, since the connotation is that there is something less real about pleiotropy caused by a single protein. But no one uses these terms anymore, so never mind. Incidentally, I previously worked with Drosophila gene expression data, and there it was evident that mRNA (which is what gets translated into protein) was found in multiple tissues (we called them domains, but think of them as traits, e.g. 'hind gut', 'glial cells', 'rectum', etc.). Studies mostly confirm that pleiotropy is largely owing to one protein's involvement in several traits, so it doesn't seem so spurious.

Stearns argues that alternative reading frames (where the DNA strand is read at different starting positions, yielding different proteins), which is common in bacteria, is an instance of pleiotropy, since there is information shared between the two 'genes'. I totally concur, since for me the issue is whether a mutation can affect more than one trait, and in this instance it certainly can, given that the different proteins affect different traits.

Current research questions about pleiotropy

One avenue of research on pleiotropy is how extensive it is. Recent research has shot down the assumption of universal pleiotropy made by the founders of the Modern Synthesis (Fisher, Wright, Mayr), which states that all genes has the potential to affect all traits. However, we now know something about the distribution of number of traits affected, i.e., the level of pleiotropy. For example, Wang, Liao, and Zhang (2010) found that in yeast, nematode and mouse, the number of traits that a gene affects ranges between 0 and about 150, with averages of up 5-8 traits for nematode and mouse.



Staerns quotes earlier studies that found the level of pleiotropy to be 4-5 (in yeast, Droshoplia and nematode), 6-7 for eight vertebrate species, and 7.8 for mouse in a study of skeletal genetics.

Since this is counting traits per gene, you may be excused for asking what a trait is (and what a gene is, but that's not my purview). For one thing, the nomenclature is a little confusing. What is meant by trait here, is what is formally known as a character, which is a property of the phenotype. Trait can sometimes mean the value of the character, such as character=hair, trait=brown, but I like to refer to that as the trait value (and I'm not alone). Phenotype can also mean two things, namely the whole physical/biological manifestation of an organism, and that's what I meant here, but it can also refer to a trait, like when they say that knocking out a particular gene causes a particular phenotype. This may all not be very enlightening if we're interested in what a trait is; the pornographic definition seems to be what people apply: "I'll recognize it when I see it". And one may wonder how many traits a species has. The caption to the figure above from Wang et al. reads

Frequency distributions of degree of gene pleiotropy in (A) yeast morphological, (B) yeast environmental, (C) yeast physiological, (D) nematode, and (E) mouse pleiotropy data. Mean and median degrees of pleiotropy and their SDs are indicated. The numbers in parentheses are the mean and median degrees of pleiotropy divided by the total number of traits. After the removal of genes that do not affect any trait and traits that are not affected by any gene, the total numbers of genes and traits in these datasets are (A) 2,449 genes and 253 traits, (B) 774 genes and 22 traits, (C) 1,256 genes and 120 traits, (D) 661 genes and 44 traits, and (E) 4,915 genes and 308 traits.

"Traits that are not affected by any gene..." Strange. Describing the methods they say

Using the yeast morphological pleiotropy data, we calculated the number (n) of traits that are significantly affected by each gene. We then measured a gene’s total phenotypic effect on these n traits, using either the Euclidian distance (TE) or the Manhattan distance (TM).

I'm not sure, but it doesn't seem that even if they looked at all 6,000 yeast genes that they then necessarily identified all traits. Their number of 253 morphological traits... is that enough to completely characterize Baker's yeast? And are 308 really enough to characterize a mouse? How many traits to humans have?

Okay, I'm done. Go.

References:
Stearns, F. (2010). One Hundred Years of Pleiotropy: A Retrospective Genetics, 186 (3), 767-773 DOI: 10.1534/genetics.110.122549
Wang, Z., Liao, B., & Zhang, J. (2010). From the Cover: Genomic patterns of pleiotropy and the evolution of complexity Proceedings of the National Academy of Sciences, 107 (42), 18034-18039 DOI: 10.1073/pnas.1004666107