De novo mutations, genetic mosaicism and human disease

Abstract

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Mosaicism—the existence of genetically distinct populations of cells in a particular organism—is an important cause of genetic disease. Mosaicism can appear as de novo DNA mutations, epigenetic alterations of DNA, and chromosomal abnormalities. Neurodevelopmental or neuropsychiatric diseases, including autism—often arise by de novo mutations that usually not present in either of the parents. De novo mutations might occur as early as in the parental germline, during embryonic, fetal development, and/or post-natally, through ageing and life. Mutation timing could lead to mutation burden of less than heterozygosity to approaching homozygosity. Developmental timing of somatic mutation attainment will affect the mutation load and distribution throughout the body. In this review, we discuss the timing of de novo mutations, spanning from mutations in the germ lineage (all ages), to post-zygotic, embryonic, fetal, and post-natal events, through aging to death. These factors can determine the tissue specific distribution and load of de novo mutations, which can affect disease. The disease threshold burden of somatic de novo mutations of a particular gene in any tissue will be important to define.

Keywords

• de novo mutation
• mosaicism
• timing of mutation
• repeat instability
• germline mutation
• somatic mutation