ORCID Profile
0000-0001-9229-7216
Current Organisation
University of Oxford
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Publisher: Springer Science and Business Media LLC
Date: 15-02-2023
DOI: 10.1038/S41467-023-36606-W
Abstract: Following the diagnosis of a paediatric disorder caused by an apparently de novo mutation, a recurrence risk of 1–2% is frequently quoted due to the possibility of parental germline mosaicism but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing in idualized recurrence risk. By combining locus-specific sequencing of multiple tissues to detect occult mosaicism with long-read sequencing to determine the parent-of-origin of the mutation, we show that we can stratify the majority of couples into one of seven discrete categories associated with substantially different risks to future offspring. Among 58 families with a single affected offspring (representing 59 de novo mutations in 49 genes), the recurrence risk for 35 (59%) was decreased below 0.1%, but increased owing to parental mixed mosaicism for 5 (9%)—that could be quantified in semen for paternal cases (recurrence risks of 5.6–12.1%). Implementation of this strategy offers the prospect of driving a major transformation in the practice of genetic counselling.
Publisher: Proceedings of the National Academy of Sciences
Date: 22-12-2009
Abstract: It is well established that all of the cis -acting sequences required for fully regulated human α-globin expression are contained within a region of ≈120 kb of conserved synteny. Here, we show that activation of this cluster in erythroid cells dramatically affects expression of apparently unrelated and noncontiguous genes in the 500 kb surrounding this domain, including a gene ( NME4 ) located 300 kb from the α-globin cluster. Changes in NME4 expression are mediated by physical cis -interactions between this gene and the α-globin regulatory elements. Polymorphic structural variation within the globin cluster, altering the number of α-globin genes, affects the pattern of NME4 expression by altering the competition for the shared α-globin regulatory elements. These findings challenge the concept that the genome is organized into discrete, insulated regulatory domains. In addition, this work has important implications for our understanding of genome evolution, the interpretation of genome-wide expression, expression-quantitative trait loci, and copy number variant analyses.
Publisher: Oxford University Press (OUP)
Date: 17-01-2013
DOI: 10.1093/HMG/DDT015
Publisher: Proceedings of the National Academy of Sciences
Date: 20-11-2013
Abstract: Harvey rat sarcoma viral oncogene homolog ( HRAS ) occupies an important place in medical history, because it was the first gene in which acquired mutations that led to activation of a normal protein were associated with cancer, making it the prototype of the now canonical oncogene mechanism. Here, we explore what happens when similar HRAS mutations occur in male germ cells, an issue of practical importance because the mutations cause a serious congenital disorder, Costello syndrome, if transmitted to offspring. We provide evidence that the mutant germ cells are positively selected, leading to an increased burden of the mutations as men age. Although there are many parallels between this germline process and classical oncogenesis, there are interesting differences of detail, which are explored in this paper.
Publisher: Proceedings of the National Academy of Sciences
Date: 08-02-2016
Abstract: A major goal in genetics is to understand the processes that shape the frequency of new mutations, particularly those causing human disease. Here, we focus on specific mutations in the male germline that, although initially rare, confer a growth or survival advantage to the stem cell, leading to clonal expansion over time: a process similar to early tumor growth and currently described only in humans. Previous studies supporting this “selfish” selection quantified mutations in sperm or testis pieces using methods that destroyed their cellular origins. Here, we pinpoint and identify pathogenic mutations directly within in idual seminiferous tubules, the structures that generate spermatozoa. This methodology provides unprecedented precision in documenting the spectrum and prevalence of selfish mutations in men’s testes.
Publisher: Public Library of Science (PLoS)
Date: 22-05-2017
Publisher: Oxford University Press (OUP)
Date: 20-08-2015
DOI: 10.1093/HMG/DDV331
Publisher: Springer Science and Business Media LLC
Date: 18-05-2201
DOI: 10.1038/NG.3304
Publisher: American Psychiatric Association Publishing
Date: 06-2013
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Anne Goriely.