A pinboard by
Nicole Nuckolls

Predoctoral Researcher, Stowers Institute for Medical Research


Exploring meiotic drive and genetic conflict, an example of an infertility causing mechanism

A gene found in fission yeast, wtf4, acts as both a poison and an antidote to ensure its transmission into the next generation. wtf4 destroys developing gametes (analogous to sperm) that don't posses it. The gene poisons all gametes, but keeps the antidote only for itself. In that way, the gene kills any gametes that don't inherit it, drastically reducing fertility. Successful completion of this research will provide a vital tool for exploring these types of selfish genes, becoming a textbook example of a mechanism of infertility.


R2d2 Drives Selfish Sweeps in the House Mouse.

Abstract: A selective sweep is the result of strong positive selection driving newly occurring or standing genetic variants to fixation, and can dramatically alter the pattern and distribution of allelic diversity in a population. Population-level sequencing data have enabled discoveries of selective sweeps associated with genes involved in recent adaptations in many species. In contrast, much debate but little evidence addresses whether "selfish" genes are capable of fixation-thereby leaving signatures identical to classical selective sweeps-despite being neutral or deleterious to organismal fitness. We previously described R2d2, a large copy-number variant that causes nonrandom segregation of mouse Chromosome 2 in females due to meiotic drive. Here we show population-genetic data consistent with a selfish sweep driven by alleles of R2d2 with high copy number (R2d2(HC)) in natural populations. We replicate this finding in multiple closed breeding populations from six outbred backgrounds segregating for R2d2 alleles. We find that R2d2(HC) rapidly increases in frequency, and in most cases becomes fixed in significantly fewer generations than can be explained by genetic drift. R2d2(HC) is also associated with significantly reduced litter sizes in heterozygous mothers, making it a true selfish allele. Our data provide direct evidence of populations actively undergoing selfish sweeps, and demonstrate that meiotic drive can rapidly alter the genomic landscape in favor of mutations with neutral or even negative effects on overall Darwinian fitness. Further study will reveal the incidence of selfish sweeps, and will elucidate the relative contributions of selfish genes, adaptation and genetic drift to evolution.

Pub.: 18 Feb '16, Pinned: 07 Aug '17

The repetitive DNA element BncDNA, enriched in the B chromosome of the cichlid fish Astatotilapia latifasciata, transcribes a potentially noncoding RNA.

Abstract: Supernumerary chromosomes have been studied in many species of eukaryotes, including the cichlid fish, Astatotilapia latifasciata. However, there are many unanswered questions about the maintenance, inheritance, and functional aspects of supernumerary chromosomes. The cichlid family has been highlighted as a model for evolutionary studies, including those that focus on mechanisms of chromosome evolution. Individuals of A. latifasciata are known to carry up to two B heterochromatic isochromosomes that are enriched in repetitive DNA and contain few intact gene sequences. We isolated and characterized a transcriptionally active repeated DNA, called B chromosome noncoding DNA (BncDNA), highly represented across all B chromosomes of A. latifasciata. BncDNA transcripts are differentially processed among six different tissues, including the production of smaller transcripts, indicating transcriptional variation may be linked to B chromosome presence and sexual phenotype. The transcript lengths and lack of similarity with known protein/gene sequences indicate BncRNA might represent a novel long noncoding RNA family (lncRNA). The potential for interaction between BncRNA and known miRNAs were computationally predicted, resulting in the identification of possible binding of this sequence in upregulated miRNAs related to the presence of B chromosomes. In conclusion, Bnc is a transcriptionally active repetitive DNA enriched in B chromosomes with potential action over B chromosome maintenance in somatic cells and meiotic drive in gametic cells.

Pub.: 14 May '16, Pinned: 07 Aug '17

Recombination in the eggs and sperm in a simultaneously hermaphroditic vertebrate.

Abstract: When there is no recombination (achiasmy) in one sex, it is in the heterogametic one. This observation is so consistent that it constitutes one of the few patterns in biology that may be regarded as a 'rule' and Haldane (Haldane 1922 J. Genet. 12, 101-109. (doi:10.1007/BF02983075)) proposed that it might be driven by selection against recombination in the sex chromosomes. Yet differences in recombination rates between the sexes (heterochiasmy) have also been reported in hermaphroditic species that lack sex chromosomes. In plants-the vast majority of which are hermaphroditic-selection at the haploid stage has been proposed to drive heterochiasmy. Yet few data are available for hermaphroditic animals, and barely any for hermaphroditic vertebrates. Here, we leverage reciprocal crosses between two black hamlets (Hypoplectrus nigricans, Serranidae), simultaneously hermaphroditic reef fishes from the wider Caribbean, to generate high-density egg- and sperm-specific linkage maps for each parent. We find globally higher recombination rates in the eggs, with dramatically pronounced heterochiasmy at the chromosome peripheries. We suggest that this pattern may be due to female meiotic drive, and that this process may be an important source of heterochiasmy in animals. We also identify a large non-recombining region that may play a role in speciation and local adaptation in Hypoplectrus.

Pub.: 16 Dec '16, Pinned: 07 Aug '17

B chromosome in Plantago lagopus Linnaeus, 1753 shows preferential transmission and accumulation through unusual processes

Abstract: Comparative Cytogenetics 11(2): 375-392 DOI: 10.3897/compcytogen.v11i2.11779 Authors: Manoj K. Dhar, Gurmeet Kour, Sanjana Kaul Abstract: Plantago lagopus is a diploid (2n = 2x =12) weed belonging to family Plantaginaceae. We reported a novel B chromosome in this species composed of 5S and 45S ribosomal DNA and other repetitive elements. In the present work, presence of B chromosome(s) was confirmed through FISH on root tip and pollen mother cells. Several experiments were done to determine the transmission of B chromosome through male and female sex tracks. Progenies derived from the reciprocal crosses between plants with (1B) and without (0B) B chromosomes were studied. The frequency of B chromosome bearing plants was significantly higher than expected, in the progeny of 1B female × 0B male. Thus, the B chromosome seems to have preferential transmission through the female sex track, which may be due to meiotic drive. One of the most intriguing aspects of the present study was the recovery of plants having more chromosomes than the standard complement of 12 chromosomes. Such plants were isolated from the progenies of B chromosome carrying plants. The origin of these plants can be explained on the basis of a two step process; formation of unreduced gametes in 1B plants and fusion of unreduced gametes with the normal gametes or other unreduced gametes. Several molecular techniques were used which unequivocally confirmed similar genetic constitution of 1B (parent) and plants with higher number of chromosomes. HTML XML PDF

Pub.: 22 May '17, Pinned: 07 Aug '17

A parasitic selfish gene that affects host promiscuity.

Abstract: Selfish genes demonstrate transmission bias and invade sexual populations despite conferring no benefit to their hosts. While the molecular genetics and evolutionary dynamics of selfish genes are reasonably well characterized, their effects on hosts are not. Homing endonuclease genes (HEGs) are one well-studied family of selfish genes that are assumed to be benign. However, we show that carrying HEGs is costly for Saccharomyces cerevisiae, demonstrating that these genetic elements are not necessarily benign but maybe parasitic. We estimate a selective load of approximately 1-2% in 'natural' niches. The second aspect we examine is the ability of HEGs to affect hosts' sexual behaviour. As all selfish genes critically rely on sex for spread, then any selfish gene correlated with increased host sexuality will enjoy a transmission advantage. While classic parasites are known to manipulate host behaviour, we are not aware of any evidence showing a selfish gene is capable of affecting host promiscuity. The data presented here show a selfish element may increase the propensity of its eukaryote host to undergo sex and along with increased rates of non-Mendelian inheritance, this may counterbalance mitotic selective load and promote spread. Demonstration that selfish genes are correlated with increased promiscuity in eukaryotes connects with ideas suggesting that selfish genes promoted the evolution of sex initially.

Pub.: 21 Sep '13, Pinned: 30 Jun '17

A century of B chromosomes in plants: so what?

Abstract: Supernumerary B chromosomes (Bs) are a major source of intraspecific variation in nuclear DNA amounts in numerous species of plants. They favour large genomes, and create polymorphisms for DNA variation in natural populations. By studying Bs we can gain useful knowledge about the organization, function and evolution of genomes. There are also significant biological questions concerning the origin and structural organization of Bs, and the way in which these selfish elements can establish themselves by exploiting the replicative machinery of their host genome nucleus.It is a sine qua non that Bs originate from the A chromosomes, in a variety of ways. We can study their modes of drive and ask how it is that chromosomes which apparently lack genes can have control over their own drive process which leads to their survival in natural populations. Molecular cytogenetic studies are opening up new avenues of investigation. Population equilibria for B frequencies are determined by a balance between accumulation and harmful effects. Bs are also subject to meiotic loss due to polysomy and to elimination at meiosis as univalents. These balancing forces can be seen in the context of host/parasite interaction, based on a dissection of the genetic elements in both As and Bs (in maize) which interact to bring about a stable equilibrium, at least for a snapshot in time.Aside from their intrinsic enigmatic properties, B chromosomes make useful experimental tools to study genome organization. Thus far they have not been exploited for their applications, other than through the use of A-B translocations used for gene mapping in maize; but there are opportunities to use them to modulate the frequency and distribution of recombination, to diploidize allopolyploids, to study centromeres and to be developed as plant artificial chromosomes; given that they can be structurally modified and their inheritance stabilized.

Pub.: 21 Aug '07, Pinned: 30 Jun '17

X chromosome drive in a widespread Palearctic woodland fly, Drosophila testacea.

Abstract: Selfish genes that bias their own transmission during meiosis can spread rapidly in populations, even if they contribute negatively to the fitness of their host. Driving X chromosomes provide a clear example of this type of selfish propagation. These chromosomes have important evolutionary and ecological consequences, and can be found in a broad range of taxa including plants, mammals, and insects. Here we report a new case of X chromosome drive (X drive) in a widespread woodland fly, Drosophila testacea. We show that males carrying the driving X (SR males) sire 80-100% female offspring, and possess a diagnostic X chromosome haplotype that is perfectly associated with the sex ratio distortion phenotype. We find that the majority of sons produced by SR males are sterile and appear to lack a Y chromosome, suggesting that meiotic defects involving the Y chromosome may underlie X drive in this species. Abnormalities in sperm cysts of SR males reflect that some spermatids are failing to develop properly, confirming that drive is acting during gametogenesis. By screening wild-caught flies using progeny sex ratios and a diagnostic marker, we demonstrate that the driving X is present in wild populations at a frequency of ~10% and that suppressors of drive are segregating in the same population. The testacea species group appears to be a hotspot for X drive, and D. testacea is a promising model to compare driving X chromosomes in closely related species, some of which may even be younger than the chromosomes themselves. This article is protected by copyright. All rights reserved.

Pub.: 13 Apr '17, Pinned: 30 Jun '17

Re-engineering the zinc fingers of PRDM9 reverses hybrid sterility in mice

Abstract: The DNA-binding protein PRDM9 directs positioning of the double-strand breaks (DSBs) that initiate meiotic recombination in mice and humans. Prdm9 is the only mammalian speciation gene yet identified and is responsible for sterility phenotypes in male hybrids of certain mouse subspecies. To investigate PRDM9 binding and its role in fertility and meiotic recombination, we humanized the DNA-binding domain of PRDM9 in C57BL/6 mice. This change repositions DSB hotspots and completely restores fertility in male hybrids. Here we show that alteration of one Prdm9 allele impacts the behaviour of DSBs controlled by the other allele at chromosome-wide scales. These effects correlate strongly with the degree to which each PRDM9 variant binds both homologues at the DSB sites it controls. Furthermore, higher genome-wide levels of such ‘symmetric’ PRDM9 binding associate with increasing fertility measures, and comparisons of individual hotspots suggest binding symmetry plays a downstream role in the recombination process. These findings reveal that subspecies-specific degradation of PRDM9 binding sites by meiotic drive, which steadily increases asymmetric PRDM9 binding, has impacts beyond simply changing hotspot positions, and strongly support a direct involvement in hybrid infertility. Because such meiotic drive occurs across mammals, PRDM9 may play a wider, yet transient, role in the early stages of speciation.

Pub.: 03 Feb '16, Pinned: 30 Jun '17

Sexual antagonism and meiotic drive cause stable linkage disequilibrium and favour reduced recombination on the X chromosome

Abstract: Sexual antagonism and meiotic drive are sex‐specific evolutionary forces with the potential to shape genomic architecture. Previous theory has found that pairing two sexually antagonistic loci or combining sexual antagonism with meiotic drive at linked autosomal loci augments genetic variation, produces stable linkage disequilibrium (LD) and favours reduced recombination. However, the influence of these two forces has not been examined on the X chromosome, which is thought to be enriched for sexual antagonism and meiotic drive. We investigate the evolution of the X chromosome under both sexual antagonism and meiotic drive with two models: in one, both loci experience sexual antagonism; in the other, we pair a meiotic drive locus with a sexually antagonistic locus. We find that LD arises between the two loci in both models, even when the two loci freely recombine in females and that driving haplotypes will be enriched for male‐beneficial alleles, further skewing sex ratios in these populations. We introduce a new measure of LD, Dz′, which accounts for population allele frequencies and is appropriate for instances where these are sex specific. Both models demonstrate that natural selection favours modifiers that reduce the recombination rate. These results inform observed patterns of congealment found on driving X chromosomes and have implications for patterns of natural variation and the evolution of recombination rates on the X chromosome.

Pub.: 04 Apr '16, Pinned: 30 Jun '17

Wolbachia-induced meiotic drive and feminization is associated with an independent occurrence of selective mitochondrial sweep in a butterfly.

Abstract: Maternally inherited Wolbachia endosymbionts manipulate arthropod reproduction in various ways. In the butterfly Eurema mandarina, a cytoplasmic incompatibility-inducing Wolbachia strain wCI and the associated mtDNA haplotypes are known to originate from the sister species Eurema hecabe, which offered a good case study for microbe-mediated hybrid introgression. Besides wCI, some females with the Z0 karyotype harbour a distinct Wolbachia strain wFem, which causes all-female production by meiotic drive and feminization. We report that a considerable proportion of E. mandarina females (65.7%) were infected with both wCI and wFem (CF) on Tanegashima Island. While females singly infected with wCI (C) produced offspring at a 1 : 1 sex ratio, CF females produced only females. Although Z-linked sequence polymorphism showed no signs of divergence between C and CF females, mtDNA split into two discrete clades; one consisted of C females and the other CF females, both of which formed a clade with E. hecabe but not with uninfected E. mandarina This suggests that CF matrilines also, but independently, experienced a selective sweep after hybrid introgression from E. hecabe Distinct evolutionary forces were suggested to have caused C and CF matrilines to diverge, which would be irreversible because of the particular phenotype of wFem.

Pub.: 02 Jun '17, Pinned: 30 Jun '17

A Pooled Sequencing Approach Identifies a Candidate Meiotic Driver in Drosophila.

Abstract: Meiotic drive occurs when a selfish element increases its transmission frequency above the Mendelian ratio by hijacking the asymmetric divisions of female meiosis. Meiotic drive causes genomic conflict and potentially has a major impact on genome evolution, but only a few drive loci of large effect have been described. New methods to reliably detect meiotic drive are therefore needed, particularly for discovering moderate-strength drivers that are likely to be more prevalent in natural populations than strong drivers. Here we report an efficient method that uses sequencing of large pools of backcross (BC1) progeny to test for deviations from Mendelian segregation genome-wide of single-nucleotide polymorphisms (SNPs) that distinguish the parental strains. We show that meiotic drive can be detected by a characteristic pattern of decay in distortion of SNP frequencies, caused by recombination unlinking the driver from distal loci. We further show that control crosses allow allele-frequency distortion caused by meiotic drive to be distinguished from distortion resulting from developmental effects. We used this approach to test whether chromosomes with extreme telomere-length differences segregate at Mendelian ratios, as telomeric regions are a potential hotspot for meiotic drive due to their roles in meiotic segregation and multiple observations of high rates of telomere sequence evolution. Using four different pairings of long and short telomere strains, we find no evidence that extreme telomere-length variation causes meiotic drive in Drosophila. However, we identify one candidate meiotic driver in a centromere-linked region that shows an ~8% increase in transmission frequency, corresponding to a ~54:46 segregation ratio. Our results show that candidate meiotic drivers of moderate strength can be readily detected and localized in pools of F1 progeny.

Pub.: 05 Mar '17, Pinned: 30 Jun '17

A Meiotic Drive Element in the Maize Pathogen Fusarium verticillioides Is Located Within a 102-kb Region of Chromosome V.

Abstract: Fusarium verticillioides is an agriculturally important fungus because of its association with maize and its propensity to contaminate grain with toxic compounds. Some isolates of the fungus harbor a meiotic drive element known as Spore killer (Sk(K)) that causes nearly all surviving meiotic progeny from an Sk(K) × Spore killer-susceptible (Sk(S)) cross to inherit the Sk(K) allele. Sk(K) has been mapped to chromosome V but the genetic element responsible for meiotic drive has yet to be identified. In this study, we used cleaved amplified polymorphic sequence markers to genotype individual progeny from an Sk(K) × Sk(S) mapping population. We also sequenced the genomes of three progeny from the mapping population to determine their single nucleotide polymorphisms. These techniques allowed us to refine the location of Sk(K) to a contiguous 102-kb interval of chromosome V, herein referred to as the Sk region. Relative to Sk(S) genotypes, Sk(K) genotypes have one extra gene within this region for a total of 42 genes. The additional gene in Sk(K) genotypes, herein named SKC1 for Spore Killer Candidate 1, is the most highly expressed gene from the Sk region during early stages of sexual development. The Sk region also has three hypervariable regions, the longest of which includes SKC1 The possibility that SKC1, or another gene from the Sk region, is an essential component of meiotic drive and spore killing is discussed.

Pub.: 19 Jun '16, Pinned: 28 Jun '17

Meiotic drive changes sperm precedence patterns in house mice: potential for male alternative mating tactics?

Abstract: With female multiple mating (polyandry), male-male competition extends to after copulation (sperm competition). Males respond to this selective pressure through physiological, morphological and behavioural adaptations. Sperm competitiveness is commonly decreased in heterozygote carriers of male meiotic drivers, selfish genetic elements that manipulate the production of gametes in males. This might give carriers an evolutionary incentive to reduce the risk of sperm competition. Here, we explore this possibility in house mice. Natural populations frequently harbour a well-characterised male driver (t haplotype), which is transmitted to 90 % of heterozygous (+/t) males' offspring. Previous research demonstrated strong detrimental effects on sperm competitiveness, and suggested that +/t males are particularly disadvantaged against wild type males when first-to-mate. Low paternity success in the first-to-mate role is expected to favour male adaptations that decrease the risk of sperm competition by preventing female remating. Genotype-specific paternity patterns (sperm precedence) could lead to genetically determined alternative reproductive tactics that can spread through gene level selection. Here, we seek confirmation that +/t males are generally disadvantaged when first-to-mate and address whether males of different genotypes differ in reproductive tactics (copulatory and morphological) to maximise individual or driver fitness. Finally, we attempt to explain the mechanistic basis for alternative sperm precedence patterns in this species.We confirmed that +/t males are weak sperm competitors when first to mate. When two +/t males competed, the second-to-mate was more successful, which contrasts with first male sperm precedence when wild type males competed. However, we found no differences between male genotypes in reproductive behaviour or morphology that were consistent with alternative reproductive tactics. Sperm of +/+ and +/t males differed with respect to in vitro sperm features. Premature hypermotility in +/t males' sperm can potentially explain why +/t males are very weak sperm competitors when first-to-mate.Our results demonstrate that meiotic drivers can have strong effects on sperm precedence patterns, and may provide a heritable basis for alternative reproductive tactics motivated by reduced sperm competitiveness. We discuss how experimental and evolutionary constraints may help explain why male genotypes did not show the predicted differences.

Pub.: 23 Jun '16, Pinned: 28 Jun '17