De novo mutation

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A de novo mutation (DNM) is any mutation or alteration in the genome of an individual organism (human, animal, plant, microbe, etc.) that was not inherited from its parents. This type of mutation spontaneously occurs during the process of DNA replication during cell division. De novo mutations, by definition, are present in the affected individual but absent from both biological parents' genomes. These mutations can occur in any cell of the offspring, but those in the germ line (eggs or sperm) can be passed on to the next generation. [1]

Contents

In most cases, such a mutation has little or no effect on the affected organism due to the redundancy and robustness of the genetic code. However, in rare cases, it can have notable and serious effects on overall health, physical appearance, and other traits. Disorders that most commonly involve de novo mutations include cri-du-chat syndrome, 1p36 deletion syndrome, genetic cancer syndromes, and certain forms of autism, among others. [2]

Rate

The rate at which de novo mutations occur is not static and can vary among different organisms and even among individuals. In humans, the average number of spontaneous mutations (not present in the parents) an infant has in its genome is approximately 43.86 DNMs. [3]

Various factors can influence this rate. For instance, a study in September 2019 by the University of Utah Health revealed that certain families have a higher spontaneous mutation rate than average. This finding indicates that the rate of de novo mutation can have a hereditary component, suggesting that it may "run in the family". [4]

Additionally, the age of parents, particularly the paternal age, can significantly impact the rate of de novo mutations. Older parents, especially fathers, tend to have a higher risk of having children with de novo mutations due to the higher number of cell divisions in the male germ line as men age. [5]

In genetic counselling, parents are often told that after having a first child with a condition caused by a de novo mutation the risk of a having a second child with the same mutation is 1 – 2%. However, this does not reflect the variation in risk among different families due to genetic mosaicism. A personalised risk assessment can now quantify people's risk, and found that the risk for most people is less than 1 in 1000. [6] [7]

Role in evolution

De novo mutations play a crucial role in evolution by providing new genetic variation upon which natural selection can act. They serve as a primary source of genetic diversity, enabling species to adapt to changing environments over time. [8]

Origin of the term

This comes from two Latin words:

Related Research Articles

<span class="mw-page-title-main">Mutation</span> Alteration in the nucleotide sequence of a genome

In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis, or meiosis or other types of damage to DNA, which then may undergo error-prone repair, cause an error during other forms of repair, or cause an error during replication. Mutations may also result from insertion or deletion of segments of DNA due to mobile genetic elements.

Molecular evolution is the process of change in the sequence composition of cellular molecules such as DNA, RNA, and proteins across generations. The field of molecular evolution uses principles of evolutionary biology and population genetics to explain patterns in these changes. Major topics in molecular evolution concern the rates and impacts of single nucleotide changes, neutral evolution vs. natural selection, origins of new genes, the genetic nature of complex traits, the genetic basis of speciation, the evolution of development, and ways that evolutionary forces influence genomic and phenotypic changes.

Gene duplication is a major mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene. Gene duplications can arise as products of several types of errors in DNA replication and repair machinery as well as through fortuitous capture by selfish genetic elements. Common sources of gene duplications include ectopic recombination, retrotransposition event, aneuploidy, polyploidy, and replication slippage.

<span class="mw-page-title-main">Single-nucleotide polymorphism</span> Single nucleotide in genomic DNA at which different sequence alternatives exist

In genetics and bioinformatics, a single-nucleotide polymorphism is a germline substitution of a single nucleotide at a specific position in the genome that is present in a sufficiently large fraction of considered population.

<span class="mw-page-title-main">Germline mutation</span> Inherited genetic variation

A germline mutation, or germinal mutation, is any detectable variation within germ cells. Mutations in these cells are the only mutations that can be passed on to offspring, when either a mutated sperm or oocyte come together to form a zygote. After this fertilization event occurs, germ cells divide rapidly to produce all of the cells in the body, causing this mutation to be present in every somatic and germline cell in the offspring; this is also known as a constitutional mutation. Germline mutation is distinct from somatic mutation.

<span class="mw-page-title-main">Mutation rate</span> Rate at which mutations occur during some unit of time

In genetics, the mutation rate is the frequency of new mutations in a single gene or organism over time. Mutation rates are not constant and are not limited to a single type of mutation; there are many different types of mutations. Mutation rates are given for specific classes of mutations. Point mutations are a class of mutations which are changes to a single base. Missense and Nonsense mutations are two subtypes of point mutations. The rate of these types of substitutions can be further subdivided into a mutation spectrum which describes the influence of the genetic context on the mutation rate.

<span class="mw-page-title-main">Heritability of autism</span>

The heritability of autism is the proportion of differences in expression of autism that can be explained by genetic variation; if the heritability of a condition is high, then the condition is considered to be primarily genetic. Autism has a strong genetic basis. Although the genetics of autism are complex, autism spectrum disorder (ASD) is explained more by multigene effects than by rare mutations with large effects.

<span class="mw-page-title-main">Causes of autism</span> Proposed causes of autism

The causes of autism are environmental or genetic factors that predispose an individual to develop autism, also known as autism spectrum disorder (ASD). Many causes of autism have been proposed, but understanding of the theory of causation of autism is incomplete. Attempts have been made to incorporate the known genetic and environmental causes into a comprehensive causative framework. ASD is a neurodevelopmental disorder marked by impairments in communicative ability and social interaction and restricted/repetitive behaviors, interests, or activities not suitable for the individual's developmental stage. The severity of symptoms and functional impairment vary between individuals.

<span class="mw-page-title-main">Gene</span> Sequence of DNA or RNA that codes for an RNA or protein product

In biology, the word gene can have several different meanings. The Mendelian gene is a basic unit of heredity and the molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protein-coding genes and noncoding genes.

A postzygotic mutation is a change in an organism's genome that is acquired during its lifespan, instead of being inherited from its parent(s) through fusion of two haploid gametes. Mutations that occur after the zygote has formed can be caused by a variety of sources that fall under two classes: spontaneous mutations and induced mutations. How detrimental a mutation is to an organism is dependent on what the mutation is, where it occurred in the genome and when it occurred.

Enquiry into the evolution of ageing, or aging, aims to explain why a detrimental process such as ageing would evolve, and why there is so much variability in the lifespans of organisms. The classical theories of evolution suggest that environmental factors, such as predation, accidents, disease, and/or starvation, ensure that most organisms living in natural settings will not live until old age, and so there will be very little pressure to conserve genetic changes that increase longevity. Natural selection will instead strongly favor genes which ensure early maturation and rapid reproduction, and the selection for genetic traits which promote molecular and cellular self-maintenance will decline with age for most organisms.

<span class="mw-page-title-main">22q13 deletion syndrome</span> Rare genetic syndrome

22q13 deletion syndrome, also known as Phelan–McDermid syndrome (PMS), is a genetic disorder caused by deletions or rearrangements on the q terminal end of chromosome 22. Any abnormal genetic variation in the q13 region that presents with significant manifestations (phenotype) typical of a terminal deletion may be diagnosed as 22q13 deletion syndrome. There is disagreement among researchers as to the exact definition of 22q13 deletion syndrome. The Developmental Synaptopathies Consortium defines PMS as being caused by SHANK3 mutations, a definition that appears to exclude terminal deletions. The requirement to include SHANK3 in the definition is supported by many but not by those who first described 22q13 deletion syndrome.

The paternal age effect is the statistical relationship between the father's age at conception and biological effects on the child. Such effects can relate to birthweight, congenital disorders, life expectancy and psychological outcomes. A 2017 review found that while severe health effects are associated with higher paternal age, the total increase in problems caused by paternal age is low. While paternal age has increased since 1960–1970, this is not seen as a major public health concern.

Germline mosaicism, also called gonadal mosaicism, is a type of genetic mosaicism where more than one set of genetic information is found specifically within the gamete cells; conversely, somatic mosaicism is a type of genetic mosaicism found in somatic cells. Germline mosaicism can be present at the same time as somatic mosaicism or individually, depending on when the conditions occur. Pure germline mosaicism refers to mosaicism found exclusively in the gametes and not in any somatic cells. Germline mosaicism can be caused either by a mutation that occurs after conception, or by epigenetic regulation, alterations to DNA such as methylation that do not involve changes in the DNA coding sequence.

<span class="mw-page-title-main">Exome sequencing</span> Sequencing of all the exons of a genome

Exome sequencing, also known as whole exome sequencing (WES), is a genomic technique for sequencing all of the protein-coding regions of genes in a genome. It consists of two steps: the first step is to select only the subset of DNA that encodes proteins. These regions are known as exons—humans have about 180,000 exons, constituting about 1% of the human genome, or approximately 30 million base pairs. The second step is to sequence the exonic DNA using any high-throughput DNA sequencing technology.

Genomic structural variation is the variation in structure of an organism's chromosome. It consists of many kinds of variation in the genome of one species, and usually includes microscopic and submicroscopic types, such as deletions, duplications, copy-number variants, insertions, inversions and translocations. Originally, a structure variation affects a sequence length about 1kb to 3Mb, which is larger than SNPs and smaller than chromosome abnormality. However, the operational range of structural variants has widened to include events > 50bp. The definition of structural variation does not imply anything about frequency or phenotypical effects. Many structural variants are associated with genetic diseases, however many are not. Recent research about SVs indicates that SVs are more difficult to detect than SNPs. Approximately 13% of the human genome is defined as structurally variant in the normal population, and there are at least 240 genes that exist as homozygous deletion polymorphisms in human populations, suggesting these genes are dispensable in humans. Rapidly accumulating evidence indicates that structural variations can comprise millions of nucleotides of heterogeneity within every genome, and are likely to make an important contribution to human diversity and disease susceptibility.

<span class="mw-page-title-main">Genome evolution</span> Process by which a genome changes in structure or size over time

Genome evolution is the process by which a genome changes in structure (sequence) or size over time. The study of genome evolution involves multiple fields such as structural analysis of the genome, the study of genomic parasites, gene and ancient genome duplications, polyploidy, and comparative genomics. Genome evolution is a constantly changing and evolving field due to the steadily growing number of sequenced genomes, both prokaryotic and eukaryotic, available to the scientific community and the public at large.

ZTTK syndrome is a rare disease caused in humans by a genetic mutation of the SON gene. Common symptoms include developmental delay and sometimes moderate to several intellectual disability.

A somatic mutation is a change in the DNA sequence of a somatic cell of a multicellular organism with dedicated reproductive cells; that is, any mutation that occurs in a cell other than a gamete, germ cell, or gametocyte. Unlike germline mutations, which can be passed on to the descendants of an organism, somatic mutations are not usually transmitted to descendants. This distinction is blurred in plants, which lack a dedicated germline, and in those animals that can reproduce asexually through mechanisms such as budding, as in members of the cnidarian genus Hydra.

SYNGAP1-related intellectual disability is a monogenetic developmental and epileptic encephalopathy that affects the central nervous system. Symptoms include intellectual disability, epilepsy, autism, sensory processing deficits, hypotonia and unstable gait.

References

  1. ↑ Veltman, Joris A.; Brunner, Han G. (2012). "De novo mutations in human genetic disease". Nature Reviews Genetics. 13 (8): 565–575. doi:10.1038/nrg3241. PMC   4110909 . PMID   22777127.
  2. ↑ Sanders, Stephan J.; Ercan-Sencicek, Gunes A.; Hus, Varun; Willsey, A. Jeremy; Murtha, Michael T.; Moreno-De-Luca, Daniela; Cho, Judy; Shi, Yunjia (2011). "Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism". Neuron. 70 (5): 863–885. doi:10.1016/j.neuron.2011.05.002. PMC   3939065 . PMID   21658581.
  3. ↑ Li, Jingjing; Oehlert, John; Snyder, Michael; Stevenson, David K.; Shaw, Gary M. (2017-04-07). "Fetal de novo mutations and preterm birth". PLOS Genetics. 13 (4): e1006689. doi: 10.1371/journal.pgen.1006689 . ISSN   1553-7390. PMC   5384656 . PMID   28388617.
  4. ↑ "Some parents pass on more mutations to their children than others". ScienceDaily. Retrieved 2022-06-05.
  5. ↑ Rahbari, R.; Wuster, A.; Lindsay, S.J.; Hurst, J.M.; Rahbari, R. (2016). "Timing, rates and spectra of human germline mutation". Nature Genetics. 48 (2): 126–133. doi:10.1038/ng.3469. PMC   4731925 . PMID   26656846.
  6. ↑ Bernkopf, Marie; Abdullah, Ummi B.; Bush, Stephen J.; Wood, Katherine A.; Ghaffari, Sahar; Giannoulatou, Eleni; Koelling, Nils; Maher, Geoffrey J.; Thibaut, Loïc M.; Williams, Jonathan; Blair, Edward M.; Kelly, Fiona Blanco; Bloss, Angela; Burkitt-Wright, Emma; Canham, Natalie (2023-02-15). "Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation". Nature Communications. 14 (1): 853. doi:10.1038/s41467-023-36606-w. ISSN   2041-1723. PMC   9932158 . PMID   36792598.
  7. ↑ Bernkopf, Marie; et al. (10 August 2023). "Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation". Nature Communications. 14 (1): 853. doi:10.1038/s41467-023-36606-w. PMC   9932158 . PMID   36792598.
  8. ↑ Hartl, Daniel L.; Clark, Andrew G. (2007). Principles of Population Genetics. Sinauer Associates. pp. 45–47. ISBN   978-0-87893-308-2.
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