On the evolution of duplicated genes: subfunctionalization vs neofunctionalization

New genes can arise by gene duplication. These events are quite common on an evolutionary time scale. In the current human population, for example, there are about 100 examples of polymorphic gene duplications. These are cases where some of us have two copies of a gene while others have only one copy (Zarrie et al., 2015). Humans have gained about 700 new genes by duplication and fixation since we diverged from chimpanzees (Demuth et al., 2006). The average rate of duplication in eukaryotes is about 0.01 events per gene per million years and the half-life of a duplicated gene is about 4 million years (Lynch and Conery, 2003).

The typical fate of these duplicated genes is to "die" by mutation or deletion. There are five possible fates [see Birth and death of genes in a hybrid frog genome]:

1. One of the genes will "die" by acquiring fatal mutations. It becomes a pseudogene.
2. One of the genes will die by deletion.
3. Both genes will survive because having extra gene product (e.g. protein) will be beneficial (gene dosage).
4. One of the genes acquires a new beneficial mutation that creates a new function and at the same time causes loss of the old function (neofunctionalization). Now both genes are retained by positive selection and the complexity of the genome has increased.
5. Both genes acquire mutations that diminish function so the genome now needs two copies of the gene in order to survive (subfunctionalization).

The birth & death scenario for the origin of new genes (and of junk DNA) dates back to Susumo Ohno in 1970 (see Meyer and Van de Peer, 2003) but it was heavily promoted by Masatochi Nei beginning in 1992 with a publication by Nei and Austin Hughes (Nei and Hughes, 1992; Nei, 2005; Nei and Rooney, 2005; Nei, 2013).

I just posted about Austin Hughes and his ideas about neutral theory and random genetic drift [Austin Hughes and Neutral Theory]. I mentioned that he was an original thinker who often disagreed with the prevailing views on molecular evolution. One of those disagreements was over the divergence of duplicated genes.

One of the standard ideas quoted above is that of neofunctionalization where one copy of the duplicated genes acquires a new function that is subsequently selected giving rise to two members of a gene family that are both under negative selection. Hughes argued that this scenario is very unlikely because it requires the accidental formation of a new function that has to occur before one copy "dies" by mutation or deletion. He had a better idea that's fully explained in the abstract of his 1994 paper (Hughes, 1994).

A widely cited model of the evolution of functionally novel proteins (here called the model of mutation during non-functionality (MDN model)) holds that, after gene duplication, one gene copy is redundant and free to accumulate substitutions at random. By chance, some of these substitutions may suit the protein encoded by such a non-functional gene to a new function, which it can subsequently assume. Several lines of evidence contradict this hypothesis: (i) comparison of expressed duplicate genes from the tetraploid frog Xenopus laevis suggests that such genes are subject to purifying selection and are thus not free to accumulate substitutions at random; (ii) in a number of multi-gene families, there is now evidence that functionally distinct proteins have arisen not as a result of chance fixation of neutral variants but rather as a result of positive Darwinian selection; and (iii) the phenomenon of gene sharing, in which a single gene encodes a protein having two distinct functions, shows that gene duplication is not a necessary prerequisite to the evolution of a new protein function. A model for the evolution of new protein is proposed under which a period of gene sharing ordinarily precedes the evolution of functionally distinct proteins. Gene duplication then allows each daughter gene to specialize for one of the functions of the ancestral gene. However, if the ancestral gene is not bifunctional, either of the following two outcomes is expected to follow gene duplication: (i) one copy will be silenced by a mutation preventing expression; or (ii) if both copies continue to be expressed, both will be subject to purifying selection, as a high proportion of nonsynonymous mutations will have a completely or partly dominant deleterious effect.

This is a clever idea. It suggests that the original gene must have had two different functions—an idea related to promiscuity [see The Evolution of Enzymes from Promiscuous Precursors]. Following a gene duplication event, the result is two genes each of which carries out two functions. It's easy to see how the loss of one function could lead to the evolution of two different essential genes with different functions.

In other words, apparent neofunctionalization is really just subfunctionalization.

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Demuth, J.P., De Bie, T., Stajich, J.E., Cristianini, N., and Hahn, M.W. (2006) The evolution of mammalian gene families. PloS one, 1:e85. [doi: 10.1371/journal.pone.0000085]

Hughes, A.L. (1994) The evolution of functionally novel proteins after gene duplication. Proc. Roy. Soc. (London) B 256:119-124. [doi: 10.1098/rspb.1994.0058 ]

Lynch, M., and Conery, J.S. (2003) The evolutionary demography of duplicate genes. J. Struct. Funct. Genomics 3:35-44. [doi: 10.1023/A:1022696612931]

Meyer, A., and Van de Peer, Y. (2003) 'Natural selection merely modified while redundancy created'–Susumu Ohno's idea of the evolutionary importance of gene and genome duplications. J. Struct. Funct. Genomics, 3:7-9. [PubMed]

Nei, M. (2005) Selectionism and neutralism in molecular evolution. Mol. Biol. Evol. 22:2318-2342. [doi: 10.1093/molbev/msi242]

Nei, M. (2013) Mutation-Driven Evolution. Oxford University Press, Oxford, UK.

Nei, M., and Hughes, A. (1992) Balanced polymorphism and evolution by the birth-and-death process in the MHC loci. Paper presented at the 11th histocompatibility workshop and conference. Oxford University Press, Oxford.

Nei, M., and Rooney, A.P. (2005) Concerted and birth-and-death evolution of multigene families. Ann. Rev. Genet. 39:121. [doi: 10.1146/annurev.genet.39.073003.112240]

Zarrei, M., MacDonald, J.R., Merico, D., and Scherer, S.W. (2015) A copy number variation map of the human genome. Nat. Rev. Genet. 16:172-183. [doi: 10.1038/nrg3871]