Birth and adaptive evolution of a hominoid gene that supports high neurotransmitter flux

Burki, Fabien; Kaessmann, Henrik

doi:10.1038/ng1431

Cited by 185 publications

(195 citation statements)

References 16 publications

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“…There is evidence 26 that GLUD1 was retroposed o23 million years ago to the X chromosome, in which it gave rise to GLUD2 through random mutations and natural selection. These mutations provided the novel enzyme with unique properties that are thought to facilitate its function in the particular milieu of the nervous system.…”

Section: Discussionmentioning

confidence: 99%

Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset

et al. 2009

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Parkinson's disease (PD), a common neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and their terminations in the basal ganglia, is thought to be related to genetic and environmental factors. Although the pathophysiology of PD neurodegeneration remains unclear, protein misfolding, mitochondrial abnormalities, glutamate dysfunction and/or oxidative stress have been implicated. In this study, we report that a rare T1492G variant in GLUD2, an X-linked gene encoding a glutamate dehydrogenase (a mitochondrial enzyme central to glutamate metabolism) that is expressed in brain (hGDH2), interacted significantly with age at PD onset in Caucasian populations. Individuals hemizygous for this GLUD2 coding change that results in substitution of Ala for Ser445 in the regulatory domain of hGDH2 developed PD 6-13 years earlier than did subjects with other genotypes in two independent Greek PD groups and one North American PD cohort. However, this effect was not present in female PD patients who were heterozygous for the DNA change. The variant enzyme, obtained by substitution of Ala for Ser445, showed an enhanced basal activity that was resistant to GTP inhibition but markedly sensitive to modification by estrogens. Thus, a gain-of-function rare polymorphism in hGDH2 hastens the onset of PD in hemizygous subjects, probably by damaging nigral cells through enhanced glutamate oxidative dehydrogenation. The lack of effect in female heterozygous PD patients could be related to a modification of the overactive variant enzyme by estrogens. INTRODUCTIONParkinson's disease (PD) affects about 1.8% of people over the age of 65 years. 1 It is clinically characterized by tremor, rigidity and bradykinesia, which often occur along with disturbances of posture and gait. 2 About 80% of PD cases are sporadic, with males being more frequently affected than females (ratio¼1.5:1).The etiology of PD remains largely unknown, although interplay of environmental toxins with genetic susceptibility may be operational. The genetic hypothesis is supported by community-based studies showing that a substantial number of PD patients have similarly affected relatives. 3,4 This was also revealed by a PD study conducted by us on Crete, 5 an island of about 0.6 million people sharing the same genetic and cultural background and a common environment. Moreover, this study suggested an oligogenic model for PD, according to which disease-predisposing alleles from two or more genes need to be present in the same individual for the disorder to be expressed.With regard to the pathophysiology of PD, several hypotheses have been proposed in an attempt to explain the degeneration of dopaminergic neurons in this disorder. One of these suggests that mitochondrial dysfunction is involved, 6 a contention supported by the recent discovery of monogenetic forms of PD resulting from mutations of

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Section: Discussionmentioning

confidence: 99%

Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset

et al. 2009

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“…There are many examples in the literature of new genes with functionality in brain and testis (Burki and Kaessmann 2004;Emerson et al 2004;Begun et al 2007;Potrzebowski et al 2008;Rosso et al 2008;Zhou et al 2008). One of the novel genes is expressed in male reproductive tissue and one was identified in brain tissues, but they were also identified in many other tissues (Table 1) and there is no statistical trend.…”

Section: Sequence Characteristics and Expression Evidencementioning

confidence: 99%

Recent de novo origin of human protein-coding genes

Knowles¹,

McLysaght²

2009

Genome Res.

276

299

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The origin of new genes is extremely important to evolutionary innovation. Most new genes arise from existing genes through duplication or recombination. The origin of new genes from noncoding DNA is extremely rare, and very few eukaryotic examples are known. We present evidence for the de novo origin of at least three human protein-coding genes since the divergence with chimp. Each of these genes has no protein-coding homologs in any other genome, but is supported by evidence from expression and, importantly, proteomics data. The absence of these genes in chimp and macaque cannot be explained by sequencing gaps or annotation error. High-quality sequence data indicate that these loci are noncoding DNA in other primates. Furthermore, chimp, gorilla, gibbon, and macaque share the same disabling sequence difference, supporting the inference that the ancestral sequence was noncoding over the alternative possibility of parallel gene inactivation in multiple primate lineages. The genes are not well characterized, but interestingly, one of them was first identified as an upregulated gene in chronic lymphocytic leukemia. This is the first evidence for entirely novel human-specific protein-coding genes originating from ancestrally noncoding sequences. We estimate that 0.075% of human genes may have originated through this mechanism leading to a total expectation of 18 such cases in a genome of 24,000 protein-coding genes.

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“…Finally, under specialization, subfunctionalization and neofunctionalization act in concert, producing two copies that are functionally distinct from each other and from the ancestral gene (11). Theoretical work has shown that different conditions can result in the retention of duplicate genes by any one of these processes (9,(12)(13)(14)(15)(16)(17), and empirical studies have uncovered numerous examples of each (11,(18)(19)(20)(21)(22)(23).…”

mentioning

confidence: 99%

Neofunctionalization of young duplicate genes in Drosophila

Assis

Bachtrog

2013

Proc. Natl. Acad. Sci. U.S.A.

191

332

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Gene duplication is a key source of genetic innovation that plays a role in the evolution of phenotypic complexity. Although several evolutionary processes can result in the long-term retention of duplicate genes, their relative contributions in nature are unknown. Here we develop a phylogenetic approach for comparing genome-wide expression profiles of closely related species to quantify the roles of conservation, neofunctionalization, subfunctionalization, and specialization in the preservation of duplicate genes. Application of our method to pairs of young duplicates in Drosophila shows that neofunctionalization, the gain of a novel function in one copy, accounts for the retention of almost twothirds of duplicate genes. Surprisingly, novel functions nearly always originate in younger (child) copies, whereas older (parent) copies possess functions similar to those of ancestral genes. Further examination of such pairs reveals a strong bias toward RNAmediated duplication events, implicating asymmetric duplication and positive selection in the evolution of new functions. Moreover, we show that young duplicate genes are expressed primarily in testes and that their expression breadth increases over evolutionary time. This finding supports the "out-of-testes" hypothesis, which posits that testes are a catalyst for the emergence of new genes that ultimately evolve functions in other tissues. Thus, our study highlights the importance of neofunctionalization and positive selection in the retention of young duplicates in Drosophila and illustrates how duplicates become incorporated into novel functional networks over evolutionary time.G ene duplication produces two copies of an existing gene.Evolutionary theory predicts that functional redundancy of duplicate genes causes one copy to undergo a brief period of relaxed selection after duplication (1). In nearly all cases, this should result in an accumulation of deleterious mutations and pseudogenization of the copy within a few million years (2). However, most sequenced eukaryotic genomes contain many functional duplicates, some of which are hundreds of millions of years old (3-8), suggesting that duplicate genes play important roles in evolution.Four processes can result in the evolutionary preservation of duplicate genes: conservation, neofunctionalization, subfunctionalization, and specialization. Under conservation, ancestral functions are maintained in both copies, likely because increased gene dosage is beneficial (1). Under neofunctionalization, one copy retains its ancestral functions, and the other acquires a novel function (1). Under subfunctionalization, mutations damage different functions of each copy, such that both copies are required to preserve all ancestral gene functions (9, 10). Finally, under specialization, subfunctionalization and neofunctionalization act in concert, producing two copies that are functionally distinct from each other and from the ancestral gene (11). Theoretical work has shown that different conditions can result in the retention of...

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Birth and adaptive evolution of a hominoid gene that supports high neurotransmitter flux

Cited by 185 publications

References 16 publications

Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset

Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset

Recent de novo origin of human protein-coding genes

Neofunctionalization of young duplicate genes in Drosophila

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