Portrait of Dr Peter Ellis

Dr Peter Ellis

Lecturer in Molecular Genetics and Reproduction

About

Dr Peter Ellis is a Lecturer in Molecular Genetics and Reproduction at the University of Kent. Key findings from his work to date include the identification of novel genes on the mouse Y chromosome that affect sperm head shape and fertility; the discovery of a genomic conflict or arms race between the X and Y chromosomes in mice as they compete to influence offspring sex ratio, which in turn has dramatically affected the structural and functional content of both chromosomes; and the identification of mechanisms regulating meiotic and post-meiotic transcriptional silencing of the sex chromosomes. His laboratory investigates the molecular biology of reproduction, the conflicting roles played by sex-linked genes in regulating this process, and the relationship between DNA damage repair mechanisms and the checkpoints governing meiotic progression. Qualifications: 

  • MA in Medical Sciences, University of Cambridge (1999) 
  • PhD, University of Cambridge (2004) 
  • PGCHE and FHEA (2016) 

https://orcid.org/0000-0001-9709-

Research interests

DNA damage repair in reproduction and cancer
Meiotic germ cells and cancer cells share a number of unusual features including the activation of specific genes (the cancer-testis antigens), the ability to tolerate high numbers of DNA strand breaks without undergoing apoptosis, and (in oocytes) a lowered stringency spindle assembly checkpoint that permits cell division even in the presence of unattached kinetochores. Dr Ellis studies the intracellular mechanisms that monitor DNA damage and chromosomal alignment during cell division in order to understand how these are perturbed in disease states. 

The role of Yq-linked genes in fertility and offspring sex ratio
Mouse chromosome arm Yq is highly ampliconic, with Yq-linked genes being present in up to ~600 copies. Deletions on Yq (Yqdel) titrate the copy number level of the ampliconic genes on this chromosome arm. Yqdel males show a dose-dependent fertility phenotype, with smaller deletions leading to mild teratozoospermia and larger deletions leading to severe teratozoospermia and infertility. In the fertile males with smaller deletions, there is an offspring sex ratio skew in favour of females. Since X and Yqdel-bearing sperm are produced in equal numbers, the skew must be due to differential fertilising capacity between X-bearing and Yqdel-bearing sperm. Dr Ellis’ work in this model system is aimed at clarifying the physiological basis of the sex ratio skew, and understanding the molecular functions of the Yq-encoded genes that regulate sex ratio. 

Mechanisms of non-Mendelian inheritance
The earliest genetic concept taught in schools is Mendel’s First Law of Segregation: that you have two copies of each gene, and an equal chance of passing on either of the copies. Dr Ellis studies how and why Mendel’s Law breaks down, allowing meiotic drive genes – so-called genetic outlaws – to bias the reproductive lottery and promote their own inheritance. Key questions to resolve are how many driving genes there are, where they are in the genome, and how they work. 

Teaching

Dr Ellis teaches on a wide range of undergraduate and postgraduate courses

  • Genetics and Evolution - BI324 
  • The Genome - BI549  (from Spring 2019/20, module convenor) 
  • Research Project - BI600  
  • Integrated Endocrinology and Metabolism - BI626  
  • The Science of Reproductive Medicine - BI841 
  • MSc Project - BI845  (module convenor) 
  • Landscapes of the Future - PO681  (guest seminar)  

Supervision

MSc-R projects available for 2019/20

both projects below joint supervision with Dr Tim Fenton

How does wrongful expression of germline genes drive HPV cancer pathology? The cancer-testis antigens are a set of genes whose expression is normally restricted to the male germline, with a diverse set of functions including cell proliferation, meiotic recombination and chromatin remodelling. Strikingly, these genes are also upregulated in a range of different cancers, where they are believed to promote cell proliferation, apoptosis resistance and genome instability via as yet uncharacterised mechanisms. This project will examine the role of one such gene, SYCP2 in the pathogenesis of epithelial cancers (cervical and oral) associated with human papilloma virus (HPV) infection. Bench fees: £1000
Are Y-linked genes the explanation for the differential prevalence of certain cancers between men and women? Many cancers show differential prevalence between men and women, including head and neck cancers associated with human papilloma virus (HPV) infection. The Y-linked oncogene Rbmy – a splicing factor that regulates multiple downstream mRNAs – has previously been associated with sex differences in liver cancer prevalence. This study will test whether this also holds true for HPV-driven cancer, and investigate Rbmy’s potential downstream targets in either or both model systems as appropriate. Bench fees: £1000

Publications

Article

  • Skinner, B. et al. (2019). A high-throughput method for unbiased quantitation and categorisation of nuclear morphology. Biology of Reproduction.
    The physical arrangement of chromatin in the nucleus is cell type and species specific; a fact
    particularly evident in sperm, in which most of the cytoplasm has been lost. Analysis of the
    characteristic falciform (‘hook shaped’) sperm in mice is important in studies of sperm
    development, hybrid sterility, infertility and toxicology. However, quantification of sperm
    shape differences typically relies on subjective manual assessment, rendering comparisons
    within and between samples difficult.

    We have developed an analysis program for morphometric analysis of asymmetric nuclei
    and characterised the sperm of mice from a range of inbred, outbred and wild-derived
    mouse strains. We find that laboratory strains have elevated sperm shape variability both
    within and between samples in comparison to wild-derived inbred strains, and that sperm
    shape in F1 offspring from a cross between CBA and C57Bl6J strains is subtly affected by
    the direction of the cross. We further show that hierarchical clustering can discriminate
    distinct sperm shapes with greater efficiency and reproducibility than even experienced
    manual assessors, and is useful both to distinguish between samples and also to identify
    different morphological classes within a single sample.

    Our approach allows for the analysis of nuclear shape with unprecedented precision and
    scale and will be widely applicable to different species and different areas of biology.
  • Skinner, B. et al. (2019). Automated nuclear cartography reveals conserved sperm chromosome territory localization across 2 million years of mouse evolution. Genes [Online] 10:109;. Available at: https://doi.org/10.3390/genes10020109.
    Measurements of nuclear organization in asymmetric nuclei in 2D images have
    traditionally been manual. This is exemplified by attempts to measure chromosome position in
    sperm samples, typically by dividing the nucleus into zones, and manually scoring which zone a
    FISH signal lies in. This is time consuming, limiting the number of nuclei that can be analyzed, and
    prone to subjectivity. We have developed a new approach for automated mapping of FISH signals
    in asymmetric nuclei, integrated into an existing image analysis tool for nuclear morphology.
    Automatic landmark detection defines equivalent structural regions in each nucleus, then dynamic
    warping of the FISH images to a common shape allows us to generate a composite of the signal
    within the entire cell population. Using this approach, we mapped the positions of the sex
    chromosomes and two autosomes in three mouse lineages (Mus musculus domesticus, Mus musculus
    musculus and Mus spretus). We found that in all three, chromosomes 11 and 19 tend to interact with
    each other, but are shielded from interactions with the sex chromosomes. This organization is
    conserved across 2 million years of mouse evolution.
  • Vernet, N. et al. (2016). Zfy genes are required for efficient meiotic sex chromosome inactivation (MSCI) in spermatocytes. Human molecular genetics [Online]. Available at: http://dx.doi.org/10.1093/hmg/ddw344.
    During spermatogenesis, germ cells that fail to synapse their chromosomes or fail to undergo meiotic sex chromosome inactivation (MSCI) are eliminated via apoptosis during mid-pachytene. Previous work showed that Y-linked genes Zfy1 and Zfy2 act as "executioners" for this checkpoint, and that wrongful expression of either gene during pachytene triggers germ cell death. Here, we show that in mice, Zfy genes are also necessary for efficient MSCI and the sex chromosomes are not correctly silenced in Zfy-deficient spermatocytes. This unexpectedly reveals a triple role for Zfy at the mid-pachytene checkpoint in which Zfy genes first promote MSCI, then monitor its progress (since if MSCI is achieved, Zfy genes will be silenced), and finally execute cells with MSCI failure. This potentially constitutes a negative feedback loop governing this critical checkpoint mechanism.
  • Skinner, B. et al. (2015). Expansion of the HSFY gene family in pig lineages: HSFY expansion in suids. BMC Genomics [Online] 16:1-11. Available at: http://doi.org/10.1186/s12864-015-1650-x.
    BACKGROUND:
    Amplified gene families on sex chromosomes can harbour genes with important biological functions, especially relating to fertility. The Y-linked heat shock transcription factor (HSFY) family has become amplified on the Y chromosome of the domestic pig (Sus scrofa), in an apparently independent event to an HSFY expansion on the Y chromosome of cattle (Bos taurus). Although the biological functions of HSFY genes are poorly understood, they appear to be involved in gametogenesis in a number of mammalian species, and, in cattle, HSFY gene copy number may correlate with levels of fertility.

    RESULTS:
    We have investigated the HSFY family in domestic pig, and other suid species including warthog, bushpig, babirusa and peccaries. The domestic pig contains at least two amplified variants of HSFY, distinguished predominantly by presence or absence of a SINE within the intron. Both these variants are expressed in testis, and both are present in approximately 50 copies each in a single cluster on the short arm of the Y. The longer form has multiple nonsense mutations rendering it likely non-functional, but many of the shorter forms still have coding potential. Other suid species also have these two variants of HSFY, and estimates of copy number suggest the HSFY family may have amplified independently twice during suid evolution.

    CONCLUSIONS:
    The HSFY genes have become amplified in multiple species lineages independently. HSFY is predominantly expressed in testis in domestic pig, a pattern conserved with cattle, in which HSFY may play a role in fertility. Further investigation of the potential associations of HSFY with fertility and testis development may be of agricultural interest.
  • Skinner, B. et al. (2015). The pig X and Y Chromosomes: structure, sequence, and evolution. Genome Research [Online] 26:130-9. Available at: http://dx.doi.org/10.1101/gr.188839.114.
    We have generated an improved assembly and gene annotation of the pig X Chromosome, and a first draft assembly of the pig Y Chromosome, by sequencing BAC and fosmid clones from Duroc animals and incorporating information from optical mapping and fiber-FISH. The X Chromosome carries 1033 annotated genes, 690 of which are protein coding. Gene order closely matches that found in primates (including humans) and carnivores (including cats and dogs), which is inferred to be ancestral. Nevertheless, several protein-coding genes present on the human X Chromosome were absent from the pig, and 38 pig-specific X-chromosomal genes were annotated, 22 of which were olfactory receptors. The pig Y-specific Chromosome sequence generated here comprises 30 megabases (Mb). A 15-Mb subset of this sequence was assembled, revealing two clusters of male-specific low copy number genes, separated by an ampliconic region including the HSFY gene family, which together make up most of the short arm. Both clusters contain palindromes with high sequence identity, presumably maintained by gene conversion. Many of the ancestral X-related genes previously reported in at least one mammalian Y Chromosome are represented either as active genes or partial sequences. This sequencing project has allowed us to identify genes--both single copy and amplified--on the pig Y Chromosome, to compare the pig X and Y Chromosomes for homologous sequences, and thereby to reveal mechanisms underlying pig X and Y Chromosome evolution.
  • Vernet, N. et al. (2014). The expression of Y-linked Zfy2 in XY mouse oocytes leads to frequent meiosis 2 defects, a high incidence of subsequent early cleavage stage arrest and infertility. Development (Cambridge, England) [Online] 141:855-66. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3912830/.
    Outbred XY(Sry-) female mice that lack Sry due to the 11 kb deletion Sry(dl1Rlb) have very limited fertility. However, five lines of outbred XY(d) females with Y chromosome deletions Y(Del(Y)1Ct)-Y(Del(Y)5Ct) that deplete the Rbmy gene cluster and repress Sry transcription were found to be of good fertility. Here we tested our expectation that the difference in fertility between XO, XY(d-1) and XY(Sry-) females would be reflected in different degrees of oocyte depletion, but this was not the case. Transgenic addition of Yp genes to XO females implicated Zfy2 as being responsible for the deleterious Y chromosomal effect on fertility. Zfy2 transcript levels were reduced in ovaries of XY(d-1) compared with XY(Sry-) females in keeping with their differing fertility. In seeking the biological basis of the impaired fertility we found that XY(Sry-), XY(d-1) and XO,Zfy2 females produce equivalent numbers of 2-cell embryos. However, in XY(Sry-) and XO,Zfy2 females the majority of embryos arrested with 2-4 cells and almost no blastocysts were produced; by contrast, XY(d-1) females produced substantially more blastocysts but fewer than XO controls. As previously documented for C57BL/6 inbred XY females, outbred XY(Sry-) and XO,Zfy2 females showed frequent failure of the second meiotic division, although this did not prevent the first cleavage. Oocyte transcriptome analysis revealed major transcriptional changes resulting from the Zfy2 transgene addition. We conclude that Zfy2-induced transcriptional changes in oocytes are sufficient to explain the more severe fertility impairment of XY as compared with XO females.
  • Ellis, P. et al. (2014). Thrifty metabolic programming in rats is induced by both maternal undernutrition and postnatal leptin treatment, but masked in the presence of both: implications for models of developmental programming. BMC genomics [Online] 15:49. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899603/pdf/1471-2164-15-49.pdf.
    BACKGROUND

    Maternal undernutrition leads to an increased risk of metabolic disorders in offspring including obesity and insulin resistance, thought to be due to a programmed thrifty phenotype which is inappropriate for a subsequent richer nutritional environment. In a rat model, both male and female offspring of undernourished mothers are programmed to become obese, however postnatal leptin treatment gives discordant results between males and females. Leptin treatment is able to rescue the adverse programming effects in the female offspring of undernourished mothers, but not in their male offspring. Additionally, in these rats, postnatal leptin treatment of offspring from normally-nourished mothers programmes their male offspring to develop obesity in later life, while there is no comparable effect in their female offspring.

    RESULTS

    We show by microarray analysis of the female liver transcriptome that both maternal undernutrition and postnatal leptin treatment independently induce a similar thrifty transcriptional programme affecting carbohydrate metabolism, amino acid metabolism and oxidative stress genes. Paradoxically, however, the combination of both stimuli restores a more normal transcriptional environment. This demonstrates that "leptin reversal" is a global phenomenon affecting all genes involved in fetal programming by maternal undernourishment and leptin treatment. The thrifty transcriptional programme was associated with pro-inflammatory markers and downregulation of adaptive immune mediators, particularly MHC class I genes, suggesting a deficit in antigen presentation in these offspring.

    CONCLUSIONS

    We propose a revised model of developmental programming reconciling the male and female observations, in which there are two competing programmes which collectively drive liver transcription. The first element is a thrifty metabolic phenotype induced by early life growth restriction independently of leptin levels. The second is a homeostatic set point calibrated in response to postnatal leptin surge, which is able to over-ride the metabolic programme. This "calibration model" for the postnatal leptin surge, if applicable in humans, may have implications for understanding responses to catch-up growth in infants. Additionally, the identification of an antigen presentation deficit associated with metabolic thriftiness may relate to a previously observed correlation between birth season (a proxy for gestational undernutrition) and infectious disease mortality in rural African communities.
  • Forsey, K. et al. (2013). Expression and localization of creatine kinase in the preimplantation embryo. Molecular reproduction and development [Online] 80:185-92. Available at: http://dx.doi.org/10.1002/mrd.22146.
    Creatine Kinase (CK) catalyses the "creatine shuttle," the reversible conversion of creatine phosphate to creatine with the liberation of ATP. This article examines the potential role of the creatine shuttle in the provision of ATP during mouse preimplantation embryo development. Using quantitative PCR, transcripts of four subunit isoforms of CK--CKM, CKB, CKMT1, and CKMT2--were detectable at all developmental stages, from the presumptive zygote to late blastocyst, but there was no obvious pattern in gene expression. By contrast, total CK biochemical activity, measured by a novel method, was relatively constant from the 2- to 8-cell stage, before exhibiting a significant decrease in activity at the blastocyst stage. Immunocytochemical studies revealed a marked association of CKB with the mitotic spindle in 2- and 4-cell mouse embryos, consistent with the proposition that the creatine shuttle plays a key role in local delivery of ATP during cytokinesis. Endogenous creatine was detected in the blastocyst at a level of 0.53 pmol/embryo. In conclusion, we believe that creatine phosphate can now be added to the list of potential sources of ATP during preimplantation development.
  • Riel, J. et al. (2013). Deficiency of the multi-copy mouse Y gene Sly causes sperm DNA damage and abnormal chromatin packaging. Journal of cell science [Online] 126:803-13. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619810/.
    In mouse and man Y chromosome deletions are frequently associated with spermatogenic defects. Mice with extensive deletions of non-pairing Y chromosome long arm (NPYq) are infertile and produce sperm with grossly misshapen heads, abnormal chromatin packaging and DNA damage. The NPYq-encoded multi-copy gene Sly controls the expression of sex chromosome genes after meiosis and Sly deficiency results in a remarkable upregulation of sex chromosome genes. Sly deficiency has been shown to be the underlying cause of the sperm head anomalies and infertility associated with NPYq gene loss, but it was not known whether it recapitulates sperm DNA damage phenotype. We produced and examined mice with transgenically (RNAi) silenced Sly and demonstrated that these mice have increased incidence of sperm with DNA damage and poorly condensed and insufficiently protaminated chromatin. We also investigated the contribution of each of the two Sly-encoded transcript variants and noted that the phenotype was only observed when both variants were knocked down, and that the phenotype was intermediate in severity compared with mice with severe NPYq deficiency. Our data demonstrate that Sly deficiency is responsible for the sperm DNA damage/chromatin packaging defects observed in mice with NPYq deletions and point to SLY proteins involvement in chromatin reprogramming during spermiogenesis, probably through their effect on the post-meiotic expression of spermiogenic genes. Considering the importance of the sperm epigenome for embryonic and fetal development and the possibility of its inter-generational transmission, our results are important for future investigations of the molecular mechanisms of this biologically and clinically important process.
  • Vernet, N. et al. (2012). Spermatid development in XO male mice with varying Y chromosome short-arm gene content: evidence for a Y gene controlling the initiation of sperm morphogenesis. Reproduction (Cambridge, England) [Online] 144:433-45. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464043/pdf/REPRO120158.pdf.
    We recently used three XO male mouse models with varying Y short-arm (Yp) gene complements, analysed at 30 days post partum, to demonstrate a Yp gene requirement for the apoptotic elimination of spermatocytes with a univalent X chromosome at the first meiotic metaphase. The three mouse models were i) XSxr(a)O in which the Yp-derived Tp(Y)1Ct(Sxr-a) sex reversal factor provides an almost complete Yp gene complement, ii) XSxr(b)O,Eif2s3y males in which Tp(Y)1Ct(Sxr-b) has a deletion completely or partially removing eight Yp genes - the Yp gene Eif2s3y has been added as a transgene to support spermatogonial proliferation, and iii) XOSry,Eif2s3y males in which the Sry transgene directs gonad development along the male pathway. In this study, we have used the same mouse models analysed at 6 weeks of age to investigate potential Yp gene involvement in spermiogenesis. We found that all three mouse models produce haploid and diploid spermatids and that the diploid spermatids showed frequent duplication of the developing acrosomal cap during the early stages. However, only in XSxr(a)O males did spermiogenesis continue to completion. Most strikingly, in XOSry,Eif2s3y males, spermatid development arrested at round spermatid step 7 so that no sperm head restructuring or tail development was observed. In contrast, in XSxr(b)O,Eif2s3y males, spermatids with substantial sperm head and tail morphogenesis could be easily found, although this was delayed compared with XSxr(a)O. We conclude that Sxr(a) (and therefore Yp) includes genetic information essential for sperm morphogenesis and that this is partially retained in Sxr(b).
  • Cocquet, J. et al. (2012). A genetic basis for a postmeiotic X versus Y chromosome intragenomic conflict in the mouse. PLoS genetics [Online] 8:e1002900. Available at: http://www.plosgenetics.org/article/fetchObject.action?uri=info:doi/10.1371/journal.pgen.1002900&representation=PDF.
    Intragenomic conflicts arise when a genetic element favours its own transmission to the detriment of others. Conflicts over sex chromosome transmission are expected to have influenced genome structure, gene regulation, and speciation. In the mouse, the existence of an intragenomic conflict between X- and Y-linked multicopy genes has long been suggested but never demonstrated. The Y-encoded multicopy gene Sly has been shown to have a predominant role in the epigenetic repression of post meiotic sex chromatin (PMSC) and, as such, represses X and Y genes, among which are its X-linked homologs Slx and Slxl1. Here, we produced mice that are deficient for both Sly and Slx/Slxl1 and observed that Slx/Slxl1 has an opposite role to that of Sly, in that it stimulates XY gene expression in spermatids. Slx/Slxl1 deficiency rescues the sperm differentiation defects and near sterility caused by Sly deficiency and vice versa. Slx/Slxl1 deficiency also causes a sex ratio distortion towards the production of male offspring that is corrected by Sly deficiency. All in all, our data show that Slx/Slxl1 and Sly have antagonistic effects during sperm differentiation and are involved in a postmeiotic intragenomic conflict that causes segregation distortion and male sterility. This is undoubtedly what drove the massive gene amplification on the mouse X and Y chromosomes. It may also be at the basis of cases of F1 male hybrid sterility where the balance between Slx/Slxl1 and Sly copy number, and therefore expression, is disrupted. To the best of our knowledge, our work is the first demonstration of a competition occurring between X and Y related genes in mammals. It also provides a biological basis for the concept that intragenomic conflict is an important evolutionary force which impacts on gene expression, genome structure, and speciation.
  • Ellis, P., Yu, Y. and Zhang, S. (2011). Transcriptional dynamics of the sex chromosomes and the search for offspring sex-specific antigens in sperm. Reproduction (Cambridge, England) [Online] 142:609-19. Available at: http://www.reproduction-online.org/content/142/5/609.full.pdf.
    The ability to pre-select offspring sex via separation of X- and Y-bearing sperm would have profound ramifications for the animal husbandry industry. No fully satisfactory method is as yet available for any species, although flow sorting is commercially viable for cattle. The discovery of antigens that distinguish X- and Y-bearing sperm, i.e. offspring sex-specific antigens (OSSAs), would allow for batched immunological separation of sperm and thus enable a safer, more widely applicable and high-throughput means of sperm sorting. This review addresses the basic processes of spermatogenesis that have complicated the search for OSSAs, in particular the syncytial development of male germ cells, and the transcriptional dynamics of the sex chromosomes during and after meiosis. We survey the various approaches taken to discover OSSA and propose that a whole-genome transcriptional approach to the problem is the most promising avenue for future research in the field.
  • Ellis, P., Bacon, J. and Affara, N. (2011). Association of Sly with sex-linked gene amplification during mouse evolution: a side effect of genomic conflict in spermatids? Human molecular genetics [Online] 20:3010-21. Available at: http://hmg.oxfordjournals.org/content/20/15/3010.full.pdf+html.
    In common with other mammalian sex chromosomes, the mouse sex chromosomes are enriched for genes with male-specific function such as testis genes. However, in mouse there has been an unprecedented expansion of ampliconic sequence containing spermatid-expressed genes. We show via a phylogenetic analysis of gene amplification on the mouse sex chromosomes that multiple families of sex-linked spermatid-expressed genes are highly amplified in Mus musculus subspecies and in two further species from the Palaearctic clade of mouse species. Ampliconic X-linked genes expressed in other cell types showed a different evolutionary trajectory, without the distinctive simultaneous amplification seen in spermatid-expressed genes. The Palaearctic gene amplification occurred concurrently with the appearance of Sly, a Yq-linked regulator of post-meiotic sex chromatin (PMSC) which acts to repress sex chromosome transcription in spermatids. Despite the gene amplification, there was comparatively little effect on transcript abundance, suggesting that the genes in question became amplified in order to overcome Sly-mediated transcriptional repression and maintain steady expression levels in spermatids. Together with the known sex-ratio effects of Yq/Sly deficiency, our results suggest that Sly is involved in a genomic conflict with one or more X-linked sex-ratio distorter genes. The recent evolution of the novel PMSC regulator Sly in mouse lineages has significant implications for the use of mouse-model systems in investigating sex chromosome dynamics in spermatids.
  • Griffin, D. et al. (2010). Transcriptional Profiling of Luteinizing Hormone Receptor-Deficient Mice Before and after Testosterone Treatment Provides Insight into the Hormonal Control of Postnatal Testicular Development and Leydig Cell Differentiation. Biology of Reproduction [Online] 82:1139-1150. Available at: http://dx.doi.org/10.1095/biolreprod.109.082099.
    Luteinizing hormone (LH) is a key regulator of male fertility through its effects on testosterone secretion by Leydig cells. Transcriptional control of this is, however, currently poorly understood. Mice in which the LH receptor is knocked out (LuRKO) show reduced testicular size, reduced testosterone, elevated serum LH, and a spermatogenic arrest that can be rescued by the administration of testosterone. Using genome-wide transcription profiling of LuRKO and control testes during postnatal development and following testosterone treatment, we show that the transcriptional effects of LH insensitivity are biphasic, with an early testosterone-independent phase and a subsequent testosterone-dependent phase. Testosterone rescue re-enables the second, testosterone-dependent phase of the normal prepubertal transcription program and permits the continuation of spermatogenesis. Examination of the earliest responses to testosterone highlights six genes that respond rapidly in a dose-dependent fashion to the androgen and that are therefore candidate regulatory genes associated with the testosterone-driven progression of spermatogenesis. In addition, our transcriptional data suggest a model for the replacement of fetal-type Leydig cells by adult-type cells during testicular development in which a testosterone feedback switch is necessary for adult Leydig cell production. LH signaling affects the timing of the switch but is not a strict requirement for Leydig cell differentiation.
  • Lopes, A. et al. (2010). The human RPS4 paralogue on Yq11.223 encodes a structurally conserved ribosomal protein and is preferentially expressed during spermatogenesis. BMC molecular biology [Online] 11:33. Available at: http://www.biomedcentral.com/content/pdf/1471-2199-11-33.pdf.
    BACKGROUND

    The Y chromosome of mammals is particularly prone to accumulate genes related to male fertility. However, the high rate of molecular evolution on this chromosome predicts reduced power to the across-species comparative approach in identifying male-specific genes that are essential for sperm production in humans. We performed a comprehensive analysis of expression of Y-linked transcripts and their X homologues in several human tissues, and in biopsies of infertile patients, in an attempt to identify new testis-specific genes involved in human spermatogenesis.

    RESULTS

    We present evidence that one of the primate-specific Y-linked ribosomal protein genes, RPS4Y2, has restricted expression in testis and prostate, in contrast with its X-linked homologue, which is ubiquitously expressed. Moreover, we have determined by highly specific quantitative real time PCR that RPS4Y2 is more highly expressed in testis biopsies containing germ cells. The in silico analysis of the promoter region of RPS4Y2 revealed several differences relative to RPS4Y1, the more widely expressed paralogue from which Y2 has originated through duplication. Finally, through comparative modelling we obtained the three dimensional models of the human S4 proteins, revealing a conserved structure. Interestingly, RPS4Y2 shows different inter-domain contacts and the potential to establish specific interactions.

    CONCLUSIONS

    These results suggest that one of the Y-linked copies of the ribosomal protein S4 is preferentially expressed during spermatogenesis and might be important for germ cell development. Even though RPS4Y2 has accumulated several amino acid changes following its duplication from RPS4Y1, approximately 35 million years ago, the evolution of the Y-encoded RPS4 proteins is structurally constrained. However, the exclusive expression pattern of RPS4Y2 and the novelties acquired at the C-terminus of the protein may indicate some degree of functional specialisation of this protein in spermatogenesis.
  • Griffin, D. et al. (2010). Transcriptional profiling of luteinizing hormone receptor-deficient mice before and after testosterone treatment provides insight into the hormonal control of postnatal testicular development and Leydig cell differentiation. Biology of reproduction [Online] 82:1139-50. Available at: http://www.biolreprod.org/content/82/6/1139.full.pdf.
    Luteinizing hormone (LH) is a key regulator of male fertility through its effects on testosterone secretion by Leydig cells. Transcriptional control of this is, however, currently poorly understood. Mice in which the LH receptor is knocked out (LuRKO) show reduced testicular size, reduced testosterone, elevated serum LH, and a spermatogenic arrest that can be rescued by the administration of testosterone. Using genome-wide transcription profiling of LuRKO and control testes during postnatal development and following testosterone treatment, we show that the transcriptional effects of LH insensitivity are biphasic, with an early testosterone-independent phase and a subsequent testosterone-dependent phase. Testosterone rescue re-enables the second, testosterone-dependent phase of the normal prepubertal transcription program and permits the continuation of spermatogenesis. Examination of the earliest responses to testosterone highlights six genes that respond rapidly in a dose-dependent fashion to the androgen and that are therefore candidate regulatory genes associated with the testosterone-driven progression of spermatogenesis. In addition, our transcriptional data suggest a model for the replacement of fetal-type Leydig cells by adult-type cells during testicular development in which a testosterone feedback switch is necessary for adult Leydig cell production. LH signaling affects the timing of the switch but is not a strict requirement for Leydig cell differentiation.
  • Cocquet, J. et al. (2010). Deficiency in the multicopy Sycp3-like X-linked genes Slx and Slxl1 causes major defects in spermatid differentiation. Molecular biology of the cell [Online] 21:3497-505. Available at: http://www.molbiolcell.org/content/21/20/3497.full.pdf.
    The human and mouse sex chromosomes are enriched in multicopy genes required for postmeiotic differentiation of round spermatids into sperm. The gene Sly is present in multiple copies on the mouse Y chromosome and encodes a protein that is required for the epigenetic regulation of postmeiotic sex chromosome expression. The X chromosome carries two multicopy genes related to Sly: Slx and Slxl1. Here we investigate the role of Slx/Slxl1 using transgenically-delivered small interfering RNAs to disrupt their function. We show that Slx and Slxl1 are important for normal sperm differentiation and male fertility. Slx/Slxl1 deficiency leads to delay in spermatid elongation and sperm release. A high proportion of delayed spermatids are eliminated via apoptosis, with a consequent reduced sperm count. The remaining spermatozoa are abnormal with impaired motility and fertilizing abilities. Microarray analyses reveal that Slx/Slxl1 deficiency affects the metabolic processes occurring in the spermatid cytoplasm but does not lead to a global perturbation of sex chromosome expression; this is in contrast with the effect of Sly deficiency which leads to an up-regulation of X and Y chromosome genes. This difference may be due to the fact that SLX/SLXL1 are cytoplasmic while SLY is found in the nucleus and cytoplasm of spermatids.
  • Cocquet, J. et al. (2009). The multicopy gene Sly represses the sex chromosomes in the male mouse germline after meiosis. PLoS biology [Online] 7:e1000244. Available at: http://www.plosbiology.org/article/fetchObject.action?uri=info:doi/10.1371/journal.pbio.1000244&representation=PDF.
    Studies of mice with Y chromosome long arm deficiencies suggest that the male-specific region (MSYq) encodes information required for sperm differentiation and postmeiotic sex chromatin repression (PSCR). Several genes have been identified on MSYq, but because they are present in more than 40 copies each, their functions cannot be investigated using traditional gene targeting. Here, we generate transgenic mice producing small interfering RNAs that specifically target the transcripts of the MSYq-encoded multicopy gene Sly (Sycp3-like Y-linked). Microarray analyses performed on these Sly-deficient males and on MSYq-deficient males show a remarkable up-regulation of sex chromosome genes in spermatids. SLY protein colocalizes with the X and Y chromatin in spermatids of normal males, and Sly deficiency leads to defective repressive marks on the sex chromatin, such as reduced levels of the heterochromatin protein CBX1 and of histone H3 methylated at lysine 9. Sly-deficient mice, just like MSYq-deficient mice, have severe impairment of sperm differentiation and are near sterile. We propose that their spermiogenesis phenotype is a consequence of the change in spermatid gene expression following Sly deficiency. To our knowledge, this is the first successful targeted disruption of the function of a multicopy gene (or of any Y gene). It shows that SLY has a predominant role in PSCR, either via direct interaction with the spermatid sex chromatin or via interaction with sex chromatin protein partners. Sly deficiency is the major underlying cause of the spectrum of anomalies identified 17 y ago in MSYq-deficient males. Our results also suggest that the expansion of sex-linked spermatid-expressed genes in mouse is a consequence of the enhancement of PSCR that accompanies Sly amplification.
  • Ferguson, L., Ellis, P. and Affara, N. (2009). Two novel mouse genes mapped to chromosome Yp are expressed specifically in spermatids. Mammalian genome : official journal of the International Mammalian Genome Society [Online] 20:193-206. Available at: http://link.springer.com/content/pdf/10.1007%2Fs00335-009-9175-8.pdf.
    The male-specific region of the Y chromosome is evolutionarily predisposed to accumulate genes important for spermatogenesis. Recent work in this laboratory identified two novel Y-linked transcripts that were upregulated in the testis in response to deletions on the chromosome arm Yq. This article reports the further characterisation of these two transcripts and their comparison to related X and autosomal genes. Both map to chromosome arm Yp, outside the Sxr ( b ) deletion interval, both are present in at least two copies on the Y, and both are expressed specifically in spermatids. Given the testicular phenotype of mice with deletions on the Y chromosome, both genes are therefore likely to function in spermatid differentiation. AK006152 is a novel mouse-specific gene with a single potential open reading frame, and it is unusual in that there appears to be no X-linked relative. H2al2y is a novel histone in the H2A superfamily and has multiple X-linked relatives and a single autosomal relative in mouse. The presence of a single X-linked copy in rat suggests that H2al amplification is mouse-specific, with the alternative explanation being an earlier amplification followed by gene loss. A phylogenetic analysis of H2al genes together with other H2A genes indicates that H2al is most closely related to the mammalian-specific H2A.Bbd family of histones. Interestingly, K (a)/K (s) analysis indicates that the X and Y members of the H2al family may be under positive selection in mouse, while the autosomal copy is under purifying selection and presumably retains the ancestral function.
  • Chausiaux, O. et al. (2008). Hypogonadal mouse, a model to study the effects of the endogenous lack of gonadotropins on apoptosis. Biology of reproduction [Online] 78:77-90. Available at: http://www.biolreprod.org/content/78/1/77.full.pdf+html.
    Testicular apoptosis is involved in the regulation of germ cell numbers, allowing optimal sperm production. Apoptosis has been described to occur in response to the absence of hormonal stimulation of the testis. Here we investigate the effect of the physiological lack of gonadotropins from birth using the hypogonadal (homozygous for the mutant allele Gnrh1(hpg)) mouse as a model. We pursued a concerted strategy using microarray analysis and RT-PCR to assess transcript levels, TUNEL to quantify the incidence of apoptosis, and Western blotting to assess the respective contribution of the extrinsic and intrinsic apoptotic pathways. Our results indicate a large increase in apoptosis of both somatic and germ cell compartments in the hpg testis, affecting Sertoli cells as well as germ cells of all ages. We confirmed our observations of Sertoli cell apoptosis using anti-Mullerian inhibiting substance staining and staining for cleaved fodrin alpha. In the somatic compartment, apoptosis is primarily regulated via the membrane receptor (extrinsic) apoptotic pathway, while in the germ cell compartment, regulation occurs via both the mitochondrial (intrinsic) and membrane receptor (extrinsic) apoptotic pathways, the latter potentially in a stage-specific manner. This study is the first report of spermatogonial apoptosis in response to gonadotropin deficiency as well as the first report of Sertoli cell apoptosis in response to gonadotropin deficiency in the mouse.
  • Ellis, P. et al. (2007). Coordinated transcriptional regulation patterns associated with infertility phenotypes in men. Journal of medical genetics [Online] 44:498-508. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597934/pdf/498.pdf.
    INTRODUCTION

    Microarray gene-expression profiling is a powerful tool for global analysis of the transcriptional consequences of disease phenotypes. Understanding the genetic correlates of particular pathological states is important for more accurate diagnosis and screening of patients, and thus for suggesting appropriate avenues of treatment. As yet, there has been little research describing gene-expression profiling of infertile and subfertile men, and thus the underlying transcriptional events involved in loss of spermatogenesis remain unclear. Here we present the results of an initial screen of 33 patients with differing spermatogenic phenotypes.

    METHODS

    Oligonucleotide array expression profiling was performed on testis biopsies for 33 patients presenting for testicular sperm extraction. Significantly regulated genes were selected using a mixed model analysis of variance. Principle components analysis and hierarchical clustering were used to interpret the resulting dataset with reference to the patient history, clinical findings and histological composition of the biopsies.

    RESULTS

    Striking patterns of coordinated gene expression were found. The most significant contains multiple germ cell-specific genes and corresponds to the degree of successful spermatogenesis in each patient, whereas a second pattern corresponds to inflammatory activity within the testis. Smaller-scale patterns were also observed, relating to unique features of the individual biopsies.
  • Ellis, P. et al. (2007). Coordinated transcriptional regulation patterns associated with infertility phenotypes in men. Journal of Medical Genetics [Online] 44:498-508. Available at: http://dx.doi.org/10.1136/jmg.2007.049650.
    Introduction: Microarray gene-expression profiling is a powerful tool for global analysis of the transcriptional consequences of disease phenotypes. Understanding the genetic correlates of particular pathological states is important for more accurate diagnosis and screening of patients, and thus for suggesting appropriate avenues of treatment. As yet, there has been little research describing gene-expression profiling of infertile and subfertile men, and thus the underlying transcriptional events involved in loss of spermatogenesis remain unclear. Here we present the results of an initial screen of 33 patients with differing spermatogenic phenotypes.
    Methods: Oligonucleotide array expression profiling was performed on testis biopsies for 33 patients presenting for testicular sperm extraction. Significantly regulated genes were selected using a mixed model analysis of variance. Principle components analysis and hierarchical clustering were used to interpret the resulting dataset with reference to the patient history, clinical findings and histological composition of the biopsies.

    Results: Striking patterns of coordinated gene expression were found. The most significant contains multiple germ cell-specific genes and corresponds to the degree of successful spermatogenesis in each patient, whereas a second pattern corresponds to inflammatory activity within the testis. Smaller-scale patterns were also observed, relating to unique features of the individual biopsies.
  • Ellis, P. et al. (2007). Bidirectional transcription of a novel chimeric gene mapping to mouse chromosome Yq. BMC evolutionary biology 7:171.
    BACKGROUND

    The male-specific region of the mouse Y chromosome long arm (MSYq) contains three known highly multi-copy X-Y homologous gene families, Ssty1/2, Sly and Asty. Deletions on MSYq lead to teratozoospermia and subfertility or infertility, with a sex ratio skew in the offspring of subfertile MSYqdel males

    RESULTS

    We report the highly unusual genomic structure of a novel MSYq locus, Orly, and a diverse set of spermatid-specific transcripts arising from copies of this locus. Orly is composed of partial copies of Ssty1, Asty and Sly arranged in sequence. The Ssty1- and Sly-derived segments are in antisense orientation relative to each other, leading to bi-directional transcription of Orly. Genome search and phylogenetic tree analysis is used to determine the order of events in mouse Yq evolution. We find that Orly is the most recent gene to arise on Yq, and that subsequently there was massive expansion in copy number of all Yq-linked genes.

    CONCLUSION

    Orly has an unprecedented chimeric structure, and generates both "forward" (Orly) and "reverse" (Orlyos) transcripts arising from the promoters at each end of the locus. The region of overlap of known Orly and Orlyos transcripts is homologous to Sly intron 2. We propose that Orly may be involved in an intragenomic conflict between mouse X and Y chromosomes, and that this process underlies the massive expansion in copy number of the genes on MSYq and their X homologues.
  • Ellis, P. and Affara, N. (2006). Spermatogenesis and sex chromosome gene content: an evolutionary perspective. Human fertility (Cambridge, England) [Online] 9:1-7. Available at: http://informahealthcare.com/doi/abs/10.1080/14647270500230114.
    Mammalian sex chromosomes are highly diverged and heteromorphic: a comparatively large and gene-rich X chromosome contrasting with a small, largely heterochromatic and degenerate Y chromosome. Both gonosomes are however uniquely important in male-specific functions such as spermatogenesis. In this review, we examine the evolutionary pressures that have driven the divergence of the sex chromosomes from their ancestral state, and show how these have shaped the gene content of both chromosomes. Their shared history of gene acquisition and loss, differentiation, degeneration and intragenomic warfare has far-reaching consequences for their functionality in spermatogenesis, and may also have potential clinical implications.
  • Turner, J. et al. (2006). Pachytene asynapsis drives meiotic sex chromosome inactivation and leads to substantial postmeiotic repression in spermatids. Developmental cell [Online] 10:521-9. Available at: http://www.sciencedirect.com/science/article/pii/S1534580706000736.
    Transcriptional silencing of the sex chromosomes during male meiosis (MSCI) is conserved among organisms with limited sex chromosome synapsis, including mammals. Since the 1990s the prevailing view has been that MSCI in mammals is transient, with sex chromosome reactivation occurring as cells exit meiosis. Recently, we found that any chromosome region unsynapsed during pachytene of male and female mouse meiosis is subject to transcriptional silencing (MSUC), and we hypothesized that MSCI is an inevitable consequence of this more general meiotic silencing mechanism. Here, we provide direct evidence that asynapsis does indeed drive MSCI. We also show that a substantial degree of transcriptional repression of the sex chromosomes is retained postmeiotically, and we provide evidence that this postmeiotic repression is a downstream consequence of MSCI/MSUC. While this postmeiotic repression occurs after the loss of MSUC-related proteins at the end of prophase, other histone modifications associated with transcriptional repression have by then become established.
  • van der Weyden, L. et al. (2006). Loss of TSLC1 causes male infertility due to a defect at the spermatid stage of spermatogenesis. Molecular and cellular biology [Online] 26:3595-609. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1447413/pdf/1514-05.pdf.
    Tumor suppressor of lung cancer 1 (TSLC1), also known as SgIGSF, IGSF4, and SynCAM, is strongly expressed in spermatogenic cells undergoing the early and late phases of spermatogenesis (spermatogonia to zygotene spermatocytes and elongating spermatids to spermiation). Using embryonic stem cell technology to generate a null mutation of Tslc1 in mice, we found that Tslc1 null male mice were infertile. Tslc1 null adult testes showed that spermatogenesis had arrested at the spermatid stage, with degenerating and apoptotic spermatids sloughing off into the lumen. In adult mice, Tslc1 null round spermatids showed evidence of normal differentiation (an acrosomal cap and F-actin polarization indistinguishable from that of wild-type spermatids); however, the surviving spermatozoa were immature, malformed, found at very low levels in the epididymis, and rarely motile. Analysis of the first wave of spermatogenesis in Tslc1 null mice showed a delay in maturation by day 22 and degeneration of round spermatids by day 28. Expression profiling of the testes revealed that Tslc1 null mice showed increases in the expression levels of genes involved in apoptosis, adhesion, and the cytoskeleton. Taken together, these data show that Tslc1 is essential for normal spermatogenesis in mice.
  • Ellis, P. et al. (2005). Deletions on mouse Yq lead to upregulation of multiple X- and Y-linked transcripts in spermatids. Human molecular genetics [Online] 14:2705-15. Available at: http://hmg.oxfordjournals.org/content/14/18/2705.full.pdf.
    Deletions on the mouse Y-chromosome long arm (MSYq) lead to teratozoospermia and in severe cases to infertility. We find that the downstream transcriptional changes in the testis resulting from the loss of MSYq-encoded transcripts involve upregulation of multiple X- and Y-linked spermatid-expressed genes, but not related autosomal genes. Therefore, this indicates that in normal males, there is a specific repression of X and Y (gonosomal) transcription in post-meiotic cells, which depends on MSYq-encoded transcripts. Together with the known sex ratio skew in favour of females in the offspring of fertile MSYqdel males, this strongly suggests the existence of an intragenomic conflict between X- and Y-linked genes. Two potential antagonists in this conflict are the X-linked multicopy gene Xmr and its multicopy MSYq-linked relative Sly, which are upregulated and downregulated, respectively, in the testes of MSYqdel males. Xmr is also expressed during meiotic sex chromosome inactivation (MSCI), indicating a link between the MSCI and the MSYq-dependent gonosomal repression in spermatids. We therefore propose that this repression and MSCI itself are evolutionary adaptations to maintain a normal sex ratio in the face of X/Y antagonism.
  • Touré, A. et al. (2005). Identification of novel Y chromosome encoded transcripts by testis transcriptome analysis of mice with deletions of the Y chromosome long arm. Genome biology [Online] 6:R102. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1414076/pdf/gb-2005-6-12-r102.pdf.
    BACKGROUND

    The male-specific region of the mouse Y chromosome long arm (MSYq) is comprised largely of repeated DNA, including multiple copies of the spermatid-expressed Ssty gene family. Large deletions of MSYq are associated with sperm head defects for which Ssty deficiency has been presumed to be responsible.

    RESULTS

    In a search for further candidate genes associated with these defects we analyzed changes in the testis transcriptome resulting from MSYq deletions, using testis cDNA microarrays. This approach, aided by accumulating mouse MSYq sequence information, identified transcripts derived from two further spermatid-expressed multicopy MSYq gene families; like Ssty, each of these new MSYq gene families has multicopy relatives on the X chromosome. The Sly family encodes a protein with homology to the chromatin-associated proteins XLR and XMR that are encoded by the X chromosomal relatives. The second MSYq gene family was identified because the transcripts hybridized to a microarrayed X chromosome-encoded testis cDNA. The X loci ('Astx') encoding this cDNA had 92-94% sequence identity to over 100 putative Y loci ('Asty') across exons and introns; only low level Asty transcription was detected. More strongly transcribed recombinant loci were identified that included Asty exons 2-4 preceded by Ssty1 exons 1, 2 and part of exon 3. Transcription from the Ssty1 promotor generated spermatid-specific transcripts that, in addition to the variable inclusion of Ssty1 and Asty exons, included additional exons because of the serendipitous presence of splice sites further downstream.

    CONCLUSION

    We identified further MSYq-encoded transcripts expressed in spermatids and deriving from multicopy Y genes, deficiency of which may underlie the defects in sperm development associated with MSYq deletions.
  • Ellis, P. et al. (2004). Modulation of the mouse testis transcriptome during postnatal development and in selected models of male infertility. Molecular human reproduction [Online] 10:271-81. Available at: http://molehr.oxfordjournals.org/content/10/4/271.full.pdf.
    The aim of this study is to develop an overview of genetic events during spermatogenesis using a novel, specifically targeted gonadal gene set. Two subtracted cDNA libraries enriched for testis specific and germ cell specific genes were constructed, characterized and sequenced. The combined libraries contain >1905 different genes, the vast majority previously uncharacterized in testis. cDNA microarray analysis of the first wave of murine spermatogenesis and of selected germ cell-deficient models was used to correlate the expression of groups of genes with the appearance of defined germ cell types, suggesting their cellular expression patterns within the testis. Real-time RT-PCR and comparison to previously known expression patterns confirmed the array-derived transcription profiles of 65 different genes, thus establishing high confidence in the profiles of the uncharacterized genes investigated in this study. A total of 1748 out of 1905 genes showed significant change during the first spermatogenic wave, demonstrating the successful targeting of the libraries to this process. These findings highlight unknown genes likely to be important in germ cell production, and demonstrate the utility of these libraries in further studies. Transcriptional analysis of well-characterized mouse models of infertility will allow us to address the causes and progression of the pathology in related human infertility phenotypes.

Book section

  • Griffin, D. and Ellis, P. (2018). The Human Y-chromosome: Evolutionary Directions and Implications for the Future of “Maleness”. in: Palermo, G. D. and Sills, E. S. eds. Intracytoplasmic Sperm Injection. Springer, pp. 183-192. Available at: https://doi.org/10.1007/978-3-319-70497-5_13.
    The human Y chromosome represents an iconic image of “maleness,” and mutation, deletion, or rearrangement of the Y often lead to attendance in infertility clinics. Its evolutionary history is however also one of gene loss, inversion, and heterochromatin accumulation. There is little argument that the Y chromosome once had the size and gene density of its partner, the X chromosome, and is thus now only a shadow of its former self. The question however revolves around whether we are observing the Y at a point on its way to oblivion, or whether it has evolved effective mechanisms to cling on to life indefinitely. There are two schools of thought: The first is that the Y has persisted for hundreds of millions of years and is going nowhere. It can, it is asserted, outsmart genetic decay without regular meiotic crossing over, and the majority of its genes show signs of evolutionary selection. Palindromic sequences along its length with near 100% identity ensure self-recombination. During its history, it has added at least eight different genes, some of which have expanded in copy number, and the Y has lost no genes since humans and chimpanzees diverged ~6 million years ago. The counterargument is that the Y chromosome is subject to higher rates of variation and inefficient selection and is degrading irreversibly. The Y chromosome in other mammals has undergone lineage-specific degradation and has already disappeared entirely in some rodent lineages, such as spiny rats and mole voles. The argument goes that there is virtually nothing left of the original human Y and that the added part of the chromosome is in fact degrading rapidly. An interesting aside to what should be really only a phenomenon of interest to evolutionary cytogeneticists is that the story often gets conflated in the popular press to assume that the alleged Y chromosome demise automatically means the demise of males. Fear not, it doesn’t. Males are here to stay, and the argument is about this strange looking chromosome alone. Everyone agrees that the Y has degraded significantly, it is now well established that it has evolved some clever mechanisms to put the brakes on. The prevailing question is how effective those brakes actually are. Even experts can’t agree and a straw poll at the 2011 International Chromosome Conference suggested an even split overall, but with more men favoring the “Y remaining” model and more women the “Y leaving” scenario.
  • Ellis, P. and Erickson, R. (2016). The Sex-Determination Pathway. in: Epstein's Inborn Errors of Development: The Molecular Basis of Clinical Disorders of Morphogenesis. Oxford University Press, pp. 161-170. Available at: https://global.oup.com/academic/product/epsteins-inborn-errors-of-development-9780199934522.
    Textbook chapter outlining the molecular pathways of sex determination
  • Ellis, P. and Erickson, R. (2016). Genetics of Sex Determination and Differentiation. in: Fetal and Neonatal Physiology. Philadelphia, US: Elsevier, pp. 1510-1519. Available at: https://elsevier.ca/product.jsp?isbn=9780323352147.
    Textbook chapter covering the molecular mechanisms of sex determination and differentiation