Infertility affects 10-15% of couples, making it one of the more common disorders for people of reproductive age. Over 20% of cases are idiopathic in nature, and it is commonly thought that many of these have an underlying genetic etiology. Identifying genes involved in unexplained infertility not only informs an understanding of the mechanisms regulating fertility, but also provides clinical information to support diagnosis, genetic counseling, and eventual therapeutic intervention. One approach to identifying genes involved in infertility is to examine the phenotype-genotype correlation in subjects with a clinical phenotype (e.g., unexplained infertility) accompanied with a de novo balanced chromosomal rearrangement, as is the foundation of the Developmental Genome Anatomy Project (DGAP, dgap.harvard.edu). One subject in this study, designated DGAP230, has oligospermia and a balanced translocation, 46,XY,t(20;22)(q13.3;q11.2). We hypothesize that the translocation breakpoints disrupt or dysregulate genes important in fertility. The goal of this proposal is to identify the gene(s) causing DGAP230's infertility, and to train a graduate student in the fields of reproductive biology and clinical genetics. We will characterize the translocation to nucleotide resolution, directing an investigation of candidate genes. We will evaluate whether any candidate genes are dysregulated and determine if altered gene expression is specifically mediated by the translocation. In order to implicate the dysregulated gene(s) in infertility, we will use mice and yeast as model organisms to determine causality of the dysregulated gene(s) in infertility and investigate the molecular mechanism underlying this phenotype. The proposed study should allow us to identify novel genes implicated in infertility, uncover mechanisms underlying its pathology, and establish a reproductive biology and clinical genetics research background in a graduate student who would like one day to establish a laboratory that further studies this clinical population.
Infertility is one of the most common disorders for people of reproductive age, and limited medical interventions are available for patients when the cause of their infertility is unknown. This work uncovers novel genetic causes of infertility using human and model organisms to identify and investigate genes that may be important for fertility. This study will improve our understanding of what causes infertility, demonstrate a new method to aid in diagnosis of other patients with unexplained infertility, and provide information for patients in our study to support their diagnosis, genetic counseling, and eventual therapeutic intervention.
|Schilit, Samantha L P; Morton, Cynthia C (2018) 3C-PCR: a novel proximity ligation-based approach to phase chromosomal rearrangement breakpoints with distal allelic variants. Hum Genet 137:55-62|