Meiotic DNA Repair and Epigenetic Remodeling of the X and Y Chromosomes Could Contribute to the 'gender Bias' in Sex-Linked Autism Spectrum Disorders

Friday, May 13, 2016: 11:30 AM-1:30 PM
Hall A (Baltimore Convention Center)
J. L. Hopkins, M. Jamabo and P. W. Jordan, Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

Autism Spectrum Disorders (ASD) exhibit a strong gender bias, whereby males are up to four times more likely to develop ASD than girls. Sex chromosome mutations have been associated with ASD, and children with sex-chromosomal aneuploidies, such as Turner [XO] and Klinefelter’s [XXY] syndromes have an increased risk of developing ASD. The majority of errors that give rise to sex-chromosome abnormalities in progeny are derived from the paternal germline during meiosis I. Therefore, genomic instability during male meiosis may represent a causal factor for genetic and/or epigenetically-linked ASD pathogenesis and its increased prevalence in males.

In order for homologous chromosomes to accurately segregate during meiosis, they must first pair, synapse, and undergo crossover recombination. During male meiosis, the X and Y chromosomes remain largely unsynapsed and lack a homologous template to facilitate canonical DNA double-strand break repair, and therefore repair and segregation of the sex chromosomes is inherently error-prone. To ensure meiotic progression, the sex chromosomes are epigenetically silenced and compartmentalized into a peripheral nuclear subdomain known as the “sex body” in a process known as “Meiotic Sex Chromosome Inactivation” (MSCI). This process is initiated and maintained by accumulation of DNA damage response proteins (DDR) on the XY chromatin-wide domains. Sex chromosome silencing persists beyond meiosis and can influence imprinting and embryonic development in the next generation.


We hypothesize that the Polo-like kinase4 (PLK4) plays a novel role in DNA repair and epigenetic reprogramming of the sex chromosomes during male meiosis, and that failure to regulate these mechanisms in the paternal germline can lead to aberrations in imprinting and/or increased de-novo mutations in sex-linked genes. These events are likely to contribute towards the molecular etiology of sex-chromosome linked ASD.


We have utilized a mutant mouse model (Plk4I242N/+) to elucidate the meiotic role of PLK4 in male germline-quality, with emphasis on MSCI. Short-term spermatocyte culture, chromosome spreads, protein, and mRNA analysis were performed using purified germ cells from Plk4I242N/+ and littermate control mice. qPCR and immunofluorescence microscopy were used to assess transcriptional silencing and condensation of the sex chromosomes in spermatocytes. Paternal X-chromosome (Xp) imprinting will be assessed at the 2-16 cell stages in WT pre-implantation embryos by using Cot1 and Xist-RNA FISH, and X-chromosome paint.


PLK4 localizes to the sex chromosomes during prophase I in males, resembling the localization patterns of DDR proteins known to be involved in MSCI. Meiotic progression, DNA damage repair, and sex-body organization and silencing is abnormal in Plk4I242N/+spermatocytes.


PLK4 regulates epigenetic remodeling and DNA repair of the sex chromosomes during MSCI. Ongoing studies will determine whether defective MSCI initiation and maintenance in spermatocytes can give rise to abnormal Xp chromosome imprinting. The precise mechanism by which these abnormalities lead to impaired brain development is not well understood. GWAS will be useful to determine whether any associations exist between parental meiosis-specific genes and increased mutations on the sex chromosomes in children. Assessment of paternal sperm quality might also be considered.

See more of: Genetics
See more of: Genetics