# Search for new genes involved in male infertility through novel approaches

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $540,499

## Abstract

SUMMARY
To date, the etiology of idiopathic male infertility is not fully understood, and hormonal male contraceptives have
not been effective. Through novel approaches to sequencing and sequencing analysis of male infertile patients
and controls, this proposal seeks to identify new coding and non-coding genes and genomic regions required for
male fertility and to validate the functional requirement of newly identified genes through mouse models. Past
limited sequencing-based approaches have so far only been able to provide diagnostic variants to 1.5% of
infertile men who present to the clinic, a yield that will improve with identification of more genes underlying
infertility in men. One limitation to past progress has been the inability of conventional short-read sequencing to
resolve haplotype-specific information: whether two or more mutations in each gene are on the same or separate
alleles. Since gene loss-of-function typically requires damage to both alleles, it is of paramount importance to be
able to resolve this information. Through long-read sequencing (a newly established and validated technology)
we will identify novel damaging mutations at haplotype-specific resolution, correlating multiple novel damaging
mutations with potential loss-of-function in our newly sequenced patients. Additionally, since sperm are haploid
and previous studies have demonstrated a requirement for newly synthesized genes after meiosis, we will
identify mutations lethal to sperm development through sequencing of both whole blood and sperm. Mutations
present in blood (representing both maternal and paternal genomes) that are absent in sperm [with haploid
genomes representing 8 million (2^23) chromosome combinations] demonstrate a requirement for those genes in
the later stages of sperm development. Thus, through our proposed work we will identify for the first-time genes
required for male fertility in men who may in fact be fertile. Lastly, we will apply CRISPR/Cas9 in mice to validate
the functional requirement of candidate genes that we identify through our sequencing studies. Novel male
infertility associated genes that are found to be expressed in sperm or epididymal cells, are evolutionarily
conserved in vertebrates, including mice and humans, and rank among the highest in our patients will be
prioritized for validation. We will assess the fertility phenotype of mutant mice and further explore molecular
pathophysiology, which for some genes may determine candidacy as a contraceptive target.

## Key facts

- **NIH application ID:** 10745335
- **Project number:** 5R01HD106056-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Thomas Garcia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $540,499
- **Award type:** 5
- **Project period:** 2022-02-22 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745335

## Citation

> US National Institutes of Health, RePORTER application 10745335, Search for new genes involved in male infertility through novel approaches (5R01HD106056-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10745335. Licensed CC0.

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