Inherently Responsive

Winning by Losing in the Human Genome?

The idea that evolution is led by increasing genetic complexity has, over the years, annealed into the general opinion of geneticists. This increasing complexity is developed through the expensive and slow innovation cycle of gene duplication, mutation, and selection; and so, it seems contrary that a species’ fitness could be improved by losing hard-won genetic capabilities, as has been proposed by the “less is more” hypothesis (Olson, 1999). For that reason, genetic research has traditionally dealt with active genes instead of “broken” ones (or pseudogenes). The lack of a deep knowledge about the genomic significance of adaptive gene losses in mammalian genome evolution explains the important contribution of a recent study in this research area (Zhu et al, 2007). This recent work applied an ingenious method to systematically identify the losses of genes that had been long established in the human lineage over the last 75 million years. A total of 26 well-established genes, inactivated long after their birth, were identified by this analysis, with the identification of 16 previously uncharacterized human pseudogenes. This work completes former studies about pseudogene formation during human origin (Wang et al, 2006), and provides important insights for a better comprehension of this particular genetic phenomenon, in a field scarcely documented until now.

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Original Article

Winning by Losing in the Human Genome?

Juan AG Ranea1*, Ian Morilla2, Corin Yeats1

1Biomolecular Structure and Modelling Group, Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, UK.

2Department of Molecular Biology and Biochemistry, University of Malaga, Spain.

*e-mail: ranea@biochemistry.ucl.ac.uk

The idea that evolution is led by increasing genetic complexity has, over the years, annealed into the general opinion of geneticists. This increasing complexity is developed through the expensive and slow innovation cycle of gene duplication, mutation, and selection; and so, it seems contrary that a species’ fitness could be improved by losing hard-won genetic capabilities, as has been proposed by the “less is more” hypothesis (Olson, 1999). For that reason, genetic research has traditionally dealt with active genes instead of “broken” ones (or pseudogenes). The lack of a deep knowledge about the genomic significance of adaptive gene losses in mammalian genome evolution explains the important contribution of a recent study in this research area (Zhu et al, 2007). This recent work applied an ingenious method to systematically identify the losses of genes that had been long established in the human lineage over the last 75 million years. A total of 26 well-established genes, inactivated long after their birth, were identified by this analysis, with the identification of 16 previously uncharacterized human pseudogenes. This work completes former studies about pseudogene formation during human origin (Wang et al, 2006), and provides important insights for a better comprehension of this particular genetic phenomenon, in a field scarcely documented until now.

The scale of adaptive gene losses identified by this study is likely underestimate: the conservative filtering criteria and limitations in the methodology applied make the analysis far more prone to produce false negative than false positive predictions. The low sensitivity of the method reflects too difficulty of obtaining genetic evidence of advantageous inactivation events. Adaptive gene loss is difficult to demonstrate since an inactivated gene can become fixed by contrasting evolutionary causes: genetic drift following the relaxation of purifying selection in functionally redundant dispensable genes; or positive selection due to shifting environmental conditions. Distinguishing adaptive losses from the remaining pseudogene pool therefore requires additional evidence of directional selection. Such evidence is difficult to obtain, since inactivated genes favoured by adaptive selection will begin to accumulate further mutations at the background neutral rate.

Although the number of cases in which we identify losses of long-established genes is likely to rise as the sensitivity of analytical techniques improves or simply as more species are studied– we must expect that they will prove to be rare genetic events. Current data points to relaxation of selection as the main cause of a gene’s inactivation, since the huge majority of the detected pseudogenes are either “dead-on-arrival” or inactivated quickly after duplication (Wang et al, 2006; Lynch and Conery, 2000).

It may be that the majority of cases involving polymorphism for inactivation of veteran or long-established genes are explained by overdominance. Classical examples (Ringelhann et al, 1976) are the higher frequency observed for some hemoglobinophaties-related human recessive alleles in high-malaria environments where heterozygosis (recessive + functional allele copies) produces a slight advantage to the disease while homozygosis (two recessive copies) causes anemia.

At least 80 genes in the human lineage appear to have been inactivated during the last 6-7 million years since the separation from chimpanzees (Wang et al, 2006). Amongst other functions, in this set of inactivated human genes there is an over-representation of chemoreception and immunity functions, consistent with the differences observed in the human senses of smell, diet, behaviour, or susceptibility to pathogens compared to chimpanzee. Presumably gene-losses are behind other human changes occurring after the separation from chimpanzees, such as a bigger brain size, bipedalism or language capability. For example, it is speculated that the reduction of the masticatory muscles, realised by the inactivation of a human myosin gene, may have allowed the hominid brain size expansion (Stedman et al, 2004).

The study of the loss of long-established genes goes far deeper into the past, over 75 millions years, encompassing the common ancestor of apes, mice and dogs (Zhu et al, 2007). The set of functions recognised for these inactivated genes is correspondingly broader. For instance, there are genes involved in hormonal regulation, cerebellum or apoptosis, suggesting changes in the human linage through the pseudogenisation of such genes. Some of these veteran genes lost in humans are known to be still functional in mouse; others may be active elsewhere in the clade, including perhaps monkeys. This is of particular significance to when it comes to use animal models for human systems that may have been affected by the gene loss.

These losses raise the intriguing question of how these long-established genes became inactive in the human lineage. Did it happen abruptly or gradually? Did it force the genetic system to compensate with a further major change? Or did a previous change in the genetic network lead to it becoming dispensable and lost? Have changes in the human environment, population size and connectedness affected the process?

References:

Lynch M, Conery JS (2000). Science 290: 1151-1155.

Olson MV (1999). Am J Hum Genet 64: 18-23.

Ringelhann B, Hathorn MK, Jilly P, Grant F, Parniczky G.A (1976). Am J Hum Genet 28: 270-279.

Stedman HH, Kozyak BW, Nelson A, Thesier DM, Su LT, Low DW, et al (2004). Nature 428: 415-418.

Wang X, Grus WE, Zhang J (2006). PLoS Biol 4: e52.

Zhu J, Sanborn JZ, Diekhans M, Lowe CB, Pringle TH, Haussler D (2007). PLoS Comput Biol 3: e247.

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