Functional evaluation of kinesin gene variants associated with female subfertility and egg aneuploidy.

Infertility is a common disease affecting 11% of reproductive-age women in the US. A leading cause of female
infertility is egg or embryo aneuploidy. Although aneuploidy rates are coupled to maternal age, aneuploidy
rates vary within a given maternal age group. Thus, for some patients, maternal age is an insufficient predictor.
Recent evidence suggests that maternal genetic variation confers predisposition to aneuploid conception.
However, no genetic test for a woman’s risk of aneuploid conception exists. Therefore, this project’s
objective is to identify causal maternal variants for predisposition to aneuploid conception. Using
whole-exome sequencing data from women with either high or low rates of aneuploid conception relative to
maternal age, we found that variants in genes encoding kinesins are overrepresented in patients with high
rates of aneuploid conception. Kinesins, microtubule-associated motor proteins, are promising candidate
genes for aneuploidy risk because they are key regulators of chromosome segregation and cell division. I
hypothesize that variants in genes encoding kinesins are causal variants in conferring predisposition to
aneuploid conception. I will address this hypothesis in Aim 1 by assessing these candidate genetic variants for
their ability to cause aneuploidy in mouse eggs and, for those that screen positive, determine the egg
development event that is disrupted. I will then evaluate the variants via in silico tools. In Aim 2, I will build
upon my preliminary data, which reveal that variants in one candidate gene, KIF18A, cause catastrophic
spindle defects in mouse eggs, and I will dissect how the kinesin motor domain of KIF18A contributes to
aneuploidy via mouse models and in silico protein structure analysis. These data will facilitate establishment of
causal maternal genetic variants in aneuploidy and provide insight into the specific mechanisms of KIF18A
motor domain variation in aneuploidy. These studies are the research training arm of a comprehensive training
plan that will build a strong foundation for a career as a physician-scientist in women’s reproductive health. Via
the proposed research, I will gain experience in rigorous and creative research approaches to egg biology, the
molecular basis of female infertility, genetic disease research in mouse models, and computational genomics.
This work will be conducted at the Human Genetics Institute of New Jersey, with state-of-the-art microscopy
facilities, modern mouse oocyte research facilities, powerful computational genetics resources, and rich faculty
expertise. My research experience will be enhanced by targeted advanced training courses in reproduction,
high-resolution microscopy, and genomics. The entirety of my training will be coupled to a longitudinal clinical
training program including reproductive endocrinology and infertility, perinatal genetics, and maternal-fetal
medicine at the state’s largest academic healthcare center, Rutgers University. The mentored research and
comprehensive training plan proposed has been carefully designed to build increasing independence for a
productive translational reproductive health career.

Grant Number: 5F30HD107976-04
NIH Institute/Center: NIH
Principal Investigator: LEELABATI BISWAS