Gene Losses during Human Origins

Pseudogenization is a widespread phenomenon in genome evolution, and it has been proposed to serve as an engine of evolutionary change, especially during human origins (the “less-is-more” hypothesis). However, there has been no comprehensive analysis of human-specific pseudogenes. Furthermore, it is unclear whether pseudogenization itself can be selectively favored and thus play an active role in human evolution. Here we conduct a comparative genomic analysis and a literature survey to identify 80 nonprocessed pseudogenes that were inactivated in the human lineage after its separation from the chimpanzee lineage. Many functions are involved among these genes, with chemoreception and immune response being outstandingly overrepresented, suggesting potential species-specific features in these aspects of human physiology. To explore the possibility of adaptive pseudogenization, we focus on CASPASE12, a cysteinyl aspartate proteinase participating in inflammatory and innate immune response to endotoxins. We provide population genetic evidence that the nearly complete fixation of a null allele at CASPASE12 has been driven by positive selection, probably because the null allele confers protection from severe sepsis. We estimate that the selective advantage of the null allele is about 0.9% and the pseudogenization started shortly before the out-of-Africa migration of modern humans. Interestingly, two other genes related to sepsis were also pseudogenized in humans, possibly by selection. These adaptive gene losses might have occurred because of changes in our environment or genetic background that altered the threat from or response to sepsis. The identification and analysis of human-specific pseudogenes open the door for understanding the roles of gene losses in human origins, and the demonstration that gene loss itself can be adaptive supports and extends the “less-is-more” hypothesis

Evolution of the Vomeronasal System Viewed through System-Specific Genes.

Using three genes specific to the vomeronasal system (VNS), I addressed three questions about the evolution of this vertebrate sensory system that were previously unanswerable with only morphological data. (1) I investigated how the V1R vomeronasal receptor repertoire evolves in mammals. (2) I investigated how the patterns of evolution in VNS receptors compare to those of the main olfactory system (MOS). (3) I investigated when the VNS originated in vertebrate evolution. For the first question, I focused on three particular aspects of mammalian V1R evolution. First, I investigated how species-specificity evolves between two closely related mammals, mouse and rat, revealing that a gene-sorting birth and death model of evolution results in many species-specific duplication and loss of V1Rs and very few orthologous mouse-rat V1R pairs. Second, I investigated V1R repertoire size variation among five orders of mammals. Dramatic variation was observed with functional repertoire size varying over 20 times between dog and mouse. This study showed a correlation between VNS morphological complexity and V1R repertoire size. Finally, I examined V1R evolution in the platypus and found that it has the largest V1R repertoire thus far identified in vertebrates. These studies revealed independent expansions in V1Rs in all three mammalian lineages. To address my second question, I compared the proportion of genes resulting from lineage-specific gene gain or loss events for nasal chemoreceptors from both vertebrate olfactory systems. With this quantitative and functional comparative study, I revealed that a significantly higher proportion of VNS receptors evolved via lineage-specific events than did MOS receptors. The evolutionary patterns observed are consistent with the differential tuning hypothesis with main olfactory receptors being broadly tuned generalists and the VNS receptors being narrowly tuned specialists. Finally, to address my third question, I investigated the phylogenetic distribution of the VNS genetic components in early diverging lineages and determined that the VNS originated in the common ancestor of vertebrates. My work highlights the utility of system-specific genes and comparative genomics in understanding the evolution of a physiological system, and presents a much richer evolutionary history of the VNS than was thought to exist by morphological data alone.Ph.D.Ecology and Evolutionary BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/60874/1/wgrus_1.pd

The Microevolution of V1r Vomeronasal Receptor Genes in Mice

Vomeronasal sensitivity is important for detecting intraspecific pheromonal cues as well as environmental odorants and is involved in mating, social interaction, and other daily activities of many vertebrates. Two large families of seven-transmembrane G-protein–coupled receptors, V1rs and V2rs, bind to various ligands to initiate vomeronasal signal transduction. Although the macroevolution of V1r and V2r genes has been well characterized throughout vertebrates, especially mammals, little is known about their microevolutionary patterns, which hampers a clear understanding of the evolutionary forces behind the rapid evolutionary turnover of V1r and V2r genes and the great diversity in receptor repertoire across species. Furthermore, the role of divergent vomeronasal perception in enhancing premating isolation and maintaining species identity has not been evaluated. Here we sequenced 44 V1r genes and 25 presumably neutral noncoding regions in 14 wild-caught mice belonging to Mus musculus and M. domesticus, two closely related species with strong yet incomplete reproductive isolation. We found that nucleotide changes in V1rs are generally under weak purifying selection and that only ∼5% of V1rs may have been subject to positive selection that promotes nonsynonymous substitutions. Consistent with the low functional constraints on V1rs, 18 of the 44 V1rs have null alleles segregating in one or both species. Together, our results demonstrate that, despite occasional actions of positive selection, the evolution of V1rs is in a large part shaped by purifying selection and random drift. These findings have broad implications for understanding the driving forces of rapid gene turnovers that are often observed in the evolution of large gene families

Intraspecific DNA Sequence Variation in Noncoding Regions Linked with the Human <i>CASP12</i> Gene

<p><i>CASPASE12</i> is shown in blue, with the exons depicted by solid blue bars on the chromosome. The premature stop codon generated by the C → T nonsense mutation is shown by an asterisk in exon 4. The nine noncoding regions sequenced are indicated below the chromosome. Exons, introns, the nine noncoding regions, and spaces between regions are drawn to scale as indicated. Red circles (connected by the red dotted line) show nucleotide diversity per site among African T alleles (π_T) and the red boxes shows π_T ± one standard error of π_T. Green squares (connected by the green dotted line) show nucleotide diversity per site among African C alleles (π_C) and the green boxes shows π_C ± one standard error of π_C. The broken green line shows the mean π_C across the nine noncoding regions sequenced. Black triangles (connected by the black solid line) show the ratio between π_T and π_C for each region. π_C is estimated from eight alleles. π_T is estimated from 22 alleles for regions 4, 5, and 6 and from eight alleles for the other regions. When only eight alleles are used, π_T is 0.00018 ± 0.00007, 0.00129 ± 0.00071, and 0.00145 ± 0.00057 for regions 4, 5, and 6, respectively. π_T is significantly lower than π_C in regions 4 and 5 (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0040052#st002" target="_blank">Table S2</a>).</p

Flow Chart for Identifying the 67 Human-Specific Nonprocessed Pseudogenes

<p>The number of pseudogenes left after each step is given in the boxes.</p

Approaches to identify genetic variants that influence the risk for onset of fragile X-associated primary ovarian insufficiency (FXPOI): a preliminary study

Fragile X-associated primary ovarian insufficiency (FXPOI) is due to an X-linked mutation that results from the expansion of a CGG repeat sequence located in the 5' untranslated region of the FMR1 gene (premutation, PM). About 20% of women who carry the PM have cessation of menses before age 40, a clinical condition known as premature ovarian failure (POF). This leads to a 20-fold increased risk over women in the general population. Thus, this single gene mutation has a major effect on reducing a woman’s reproductive life span. Based on survival analysis of about 1300 women, we showed that the mean age at menopause among PM carriers is reduced compared with noncarriers, even after removing women who reported POF. This suggests that the majority of women with the PM, not just a subset, experience ovarian insufficiency earlier than noncarriers. To better understand the underlying mechanism of the PM and to identify genes that modify the variable expressivity of FXPOI, we conducted two pilot studies. The first focused on five common variants known to reduce age at menopause. We genotyped these SNPs in 72 women with a PM who experienced menopause and found a significant association with the total SNP risk burden and age at menopause. This suggests that these SNPs influence onset of FXPOI, after adjusting for the effect of the PM allele. In the second approach, we conducted whole genome sequencing on ten PM carriers, five with onset of FXPOI prior to age 30 and five who experienced menopause after age 47 years. Although only a pilot study, we describe our preliminary approach to identify potential variants that may play a role in modifying onset of FXPOI and potentially play a role in idiopathic primary ovarian insufficiency. The overarching goal of both approaches is to identify predictor variants that may identify women predisposed to early onset FXPOI and to further identify genes involved in defining a woman’s reproductive life span

Distinct Evolutionary Patterns between Chemoreceptors of 2 Vertebrate Olfactory Systems and the Differential Tuning Hypothesis

Most tetrapod vertebrates have 2 olfactory systems, the main olfactory system (MOS) and the vomeronasal system (VNS). According to the dual olfactory hypothesis, the MOS detects environmental odorants, whereas the VNS recognizes intraspecific pheromonal cues. However, this strict functional distinction has been blurred by recent reports that both systems can perceive both types of signals. Studies of a limited number of receptors suggest that MOS receptors are broadly tuned generalists, whereas VNS receptors are narrowly tuned specialists. However, whether this distinction applies to all MOS and VNS receptors remains unknown. The differential tuning hypothesis predicts that generalist MOS receptors detect an overlapping set of ligands and thus are more likely to be conserved over evolutionary time than specialist VNS receptors, which would evolve in a more lineage-specific manner. Here we test this prediction for all olfactory chemoreceptors by examining the evolutionary patterns of MOS-expressed odorant receptors (ORs) and trace amine–associated receptors (TAARs) and VNS-expressed vomeronasal type 1 receptors (V1Rs) and vomeronasal type 2 receptors (V2Rs) in 7 tetrapods (mouse, rat, dog, opossum, platypus, chicken, and frog). The phylogenies of V1Rs and V2Rs show abundant lineage-specific gene gains/losses and virtually no one-to-one orthologs between species. Opposite patterns are found for ORs and TAARs. Analysis of functional data and ligand-binding sites of ORs confirms that paralogous chemoreceptors are more likely than orthologs to have different ligands and that functional divergence between paralogous chemoreceptors is established relatively quickly following gene duplication. Together, these results strongly suggest that the functional profile of the VNS chemoreceptor repertoire evolves much faster than that of the MOS chemoreceptor repertoire and that the differential tuning hypothesis applies to the majority, if not all, of MOS and VNS receptors