NIH grant: Molecular Consequences of Sex Chromosome Copy Number Variation (1R35GM165325-01)

retained text

NIH grant 1R35GM165325-01: Molecular Consequences of Sex Chromosome Copy Number Variation
Institute: {'code': 'GM', 'abbreviation': 'NIGMS', 'name': 'National Institute of General Medical Sciences', 'admin_org_id': '12500024', 'admin_funding_url': ''}. PI: Adrianna K San Roman. Award: $444125.
Start: 2026-08-01T00:00:00.
PROJECT SUMMARY
Sex chromosome copy number is the largest source of genetic variation in humans, correlated
with widespread differences in health and between females (46,XX) and males (46,XY). Our
research aims to define the fundamental molecular mechanisms by which this genetic variation
impacts human biology. A major challenge is disentangling the direct genetic effects from
correlated factors such as hormones or the environment. To address this, we developed a
human cell culture model from individuals with natural variation in sex chromosome number
(one to four Xs and zero to four Ys) cultured under identical conditions to isolate genetic
contributions. We discovered that sex chromosome dosage affects ~ 20% of autosomal genes,
with X copy number having 2-3 times greater impact than Y. By assessing X- and Y-linked
genes, we identified a small set of highly constrained, evolutionary conserved regulators that
differ by sex. In my newly established laboratory, we will investigate how dosage differences of
these factors contribute to human sex differences. We will start with a key pair of these
candidates – the only transcription factors that remained broadly expressed from both the X and
Y chromosomes as they evolved from ordinary autosomes – ZFX and ZFY. Their DNA binding
motifs are enriched in promoters of X- or Y-responsive autosomal genes, and CRISPR
knockdowns revealed that ZFX has a greater transcriptional impact than ZFY, leading to the
hypothesis that their evolutionary divergence drives differences in gene regulation between
males and females. We will compare the molecular features of ZFX and ZFY, explore their
evolutionary trajectories, and dissect their regulatory interactions using biochemical, proteomic,
functional genomic, and computational approaches. This work will establish a framework for
investigating additional factors, pathways, and molecular mechanisms underlying sex
differences. These efforts have the potential to transform our understanding of human biology
and influence the development of therapies for a wide range of sex-biased conditions, such as
cancer and autoimmune disease.

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