Department of Genetics
Washington University School of Medicine
4515 McKinley Avenue
St. Louis, MO 63110
phone: +1 314-362-4379
FAX: +1 314-362-7855
Assoc. Prof. Don Conrad’s lab aims to promote interdisciplinary research by integrating expertise from wetlab, bioinformatics and clinical collaborators. The main focus in the field of male infertility currently includes overseeing the Genomics of Male Infertility Initiative (GEMINI) study aiming to map the genetic causes of idiopathic severe male infertility. The GEMINI network includes 15 andrology and research centres across the world providing access to a large sample set of the cases (currently n=3000). To date, 1000 patients of non-obstructive azoospermia have been analysed on a whole-exome sequencing platform at Washington University in St. Louis. Identification and interpretation of the generated large-scale sequencing data is facilitated by the access to the high-throughput computing facility and the availability of bioinformatics research tools developed in the Conrad lab previously (Wilfert et al. Nat Genet. 2016 Dec;48(12):1455-1461). In addition to genomics research, the Conrad lab holds expertise in developing and implementing a spectrum of novel methods for analysing the molecular and genetic properties of the germline, such as single-cell RNA sequencing of germ cell populations, in vivo siRNA knock-down of target genes in mouse testis, good quality purification of male germ cell populations from various species and de novo mutation detection from small pools of germ cells. Furthermore, the group aims to maintain the interdisciplinary profile by validating a multitude of NOA candidate genes identified in the framework of the GEMINI study in model organisms. Functional follow-up of potential mutations is done in Drosophila by the Conrad lab, whereas validation studies on mouse, zebrafish and Chlamydomonas are undertaken in collaboration with local and international research groups.
Nagirnaja L, Aston KI, Conrad DF. Genetic intersection of male infertility and cancer. Fertil Steril. 2018 Jan;109(1):20-26.
Nagirnaja L, Vigh-Conrad K, Conrad DF. How to Map the Genetic Basis for Conditions that are Comorbid with Male Infertility. Semin Reprod Med. 2017 May;35(3):225-230.
Ho NR, Huang N, Conrad DF. Improved detection of disease-associated variation by sex-specific characterization and prediction of genes required for fertility. Andrology. 2015 Nov;3(6):1140-9.
Ni B, Lin Y, Sun L, Zhu M, Li Z, Wang H, Yu J, Guo X, Zuo X, Dong J, Xia Y, Wen Y, Wu H, Li H, Zhu Y, Ping P, Chen X, Dai J, Jiang Y, Xu P, Du Q, Yao B, Weng N, Lu H, Wang Z, Zhu X, Yang X, Xiong C, Ma H, Jin G, Xu J, Wang X, Zhou Z, Liu J, Zhang X, Conrad DF, Hu Z, Sha J. Low-frequency germline variants across 6p22.2-6p21.33 are associated with non-obstructive azoospermia in Han Chinese men. Hum Mol Genet. 2015 Oct 1;24(19):5628-36.
Lima AC, Carvalho F, Gonçalves J, Fernandes S, Marques PI, Sousa M, Barros A, Seixas S, Amorim A, Conrad DF, Lopes AM. Rare double sex and mab-3-related transcription factor 1 regulatory variants in severe spermatogenic failure. Andrology. 2015 Sep;3(5):825-33.
Lopes AM, Aston KI, Thompson E, Carvalho F, Gonçalves J, Huang N, Matthiesen R, Noordam MJ, Quintela I, Ramu A, Seabra C, Wilfert AB, Dai J, Downie JM, Fernandes S, Guo X, Sha J, Amorim A, Barros A, Carracedo A, Hu Z, Hurles ME, Moskovtsev S, Ober C, Paduch DA, Schiffman JD, Schlegel PN, Sousa M, Carrell DT, Conrad DF. Human spermatogenic failure purges deleterious mutation load from the autosomes and both sex chromosomes, including the gene DMRT1. PLoS Genet. 2013 Mar;9(3):e1003349.
R01MH101810 (PI Conrad) 08/01/13-06/30/18
Title: Modeling the effects of structural variation in GTEx data and Mendelian Disease
This is a proposal to integrate structural variation into the analysis of the Genotype Tissue Expression (GTEx) project data. Our project will produce a statistical model relating features of CNV to the likelihood that it disrupts gene expression. This tool can be used to improve pathogenicity assessment for rare CNVs.
R01HG007178 (PI Conrad) 05/08/14-02/28/19
Title: Analysis of de novo mutation from sequencing of related individuals and cells
We are using this grant to develop software for detecting de novo DNA mutations in next-generation sequencing data produced from related individuals, tissues and single cells.
R01HD078641 (PI Conrad) 09/10/14-05/31/19
Title: Genomics of Spermatogenic Impairment
The goal of this project is to use genome-scale next-generation sequencing to improve our understanding of the genomic basis of Spermatogenic failure (SF), and to establish the framework required to integrate genome data into the clinical management of male infertility.
MC-II-2016-533 (PI Mitra) 02/01/16 – 01/31/19
Children’s Discovery Institute
Title: Sex-specific Super Enhancer Activity in Glioblastoma
The goals of this project are to improve our understanding of sex differences in susceptibility to glioblastoma. We will map sex differences in the transcriptional programs of neurons, and identify which of these differences contribute to sex differences in the thresholds for transformation of normal neurons into cancerous ones. We will then use single-cell RNAseq to compare the expression profiles of wild type neurons to those that have been edited at genes thought to modulate expression differences between the sexes.
U54HD087011-01 (PIs: Constantino, Schlaggar) 9/1/15-8/31/20
Title: Washington University IDDRC