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A germline mutation is any detectable and heritable variation of DNA in the lineage of germ cells, special tissue that is set aside in the course of development to form sex cells (egg or spermatozoa).  If these germ cells participate in fertilization, their mutation will be transmitted to offspring, while mutations in somatic cells are not.[1] When transmitted to an offspring, a germline mutation is incorporated in the DNA of every cell of the offspring’s body. [2] These mutations maybe beneficial, harmful, or have no effect on the offspring. Germline mutations are mostly detected when they produce genetic diseases in offspring.[3]

Germ cells are formed through meiosis, a process by which diploid cells give rise to haploid gametes. The overall sequence of events in male (spermatogenesis) and female (oogenesis) meiosis is the same; however, the timing of gametogenesis is very different in two sexes. Most germline mutations occur during meiosis.[4]

Meiosis Overview: In meiosis, the chromosomes duplicate (during interphase) and homologous chromosomes exchange genetic information (chromosomal crossover) before a first division, called meiosis I. The daughter cells divide again in meiosis II, splitting up sister chromatids to form haploid gametes. Male and female gametes fuse during fertilization, creating a diploid cell with a complete set of paired chromosomes.

Inherited variation in DNA are caused by chromosomal crossover and homologous recombination that occur specifically at meiosis 1[5]. These mechanisms can cause [6]:

·     Single Nucleotide Polymorphism: A change in DNA sequence at a single base pair in DNA with a frequency that exceeds 1% in a population.

·     Insert-Deletion Polymorphism: An insertion or deletion of anywhere in the genome from a single base pair (bp) up to approximately 1000 bp.

·     Copy Number Variation: a variation in the number of copies of larger segments of the genome, ranging in size from 1000 bp to many hundreds of kilo pairs.

·     Inversion Polymorphism: a rearrangement in which a DNA segment is reversed end to end.

Alteration in the number of chromosomes (polyploidy) can also cause mutation in germ cells.[7]

Germline mutation can also occur after fertilization due to de novo mutation, a new mutation in a coding exon of an offspring gene that neither parent carries.[8] This variant can be pathogenic and cause genetic diseases. However, since between 1 and 2 new mutations occur in the coding regions of genes in every child, the fact that a mutation is de novo does not definitely mean that it is pathogenic.[9]

Mutation rates

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The overall rate of new mutation (including both harmful and benign mutations) averaged between maternal and paternal gametes is approximately 1.2 x 10-8 mutations per base pair per generation. Thus every person is likely to receive approximately 75 new mutations in his or her genome from one or the other parent. [10] The rate of gene mutations that cause disease has been estimated for a number of disorders, with an average of 10-4 to 10-7 mutations per locus per generation.[11]. Selected human disease genes that have been estimated for mutation rates are: FGFR3 (fibroblast growth factor receptor 3) with a 1.4 x 10-5rate of mutation in Achondroplasia [12]and F8 (factor VIII) with a 3.2 - 5.7 x 10-5 rate of mutation in Hemophilia A. Factors that contribute to this range are: size of gene, the age and sex of the parent in whom the mutation occurred, the mutational mechanism, and the presence or absence of mutational hot spots [13] in the gene. [14]

Mutation Bias

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Since there is sexual dimorphism in gametogenesis between the father and the mother, the effects of germline mutation are altered accordingly.[15] New sperms are formed every 15-16 days from a continuous nature of cell division; while eggs arise from a finite number of 22 -23

cell divisions[16]. As males get older, they go through more cycles of spermatogenesis, which gives place for more replication errors to occur. There is a linear relation between the father’s age and the rate of mutation: germline mutation rate increases with father’s age.[17] This linear relation occurs in the maternal germline only in chromosomal aneuploidy mutations: the risk of an offspring having Down syndrome (trisomy of chromosome 21) increases exponentially with the mother’s age. [18]

Screening

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Advances in technology that allows [wide analysis] to be done effectively and efficiently have opened door for research on germline mutation. Whole genome sequencing (WGS) can directly determine germline mutation type and frequency in a population at all loci simultaneously. In clinical trials, WGS is used to identify novel mutation to infer candidates genes contributing to inherited conditions. However, the cost of WGS is still relatively high and required a large sample size. Despite currently being the most advanced technique in DNA sequencing, WGS still has high error rates: with every true mutation, there are 10-1013 false positives detection.[19]

See Also:

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Notes

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  1. ^ Campbell, D. C.; Eichler, E. E. 2013. “Properties and rates of germline mutation in humans.” Trends in Genetics 29(10): 575 - 584. doi:10.1016/j.tig.2013.04.005.    
  2. ^ "National Cancer Institute".
  3. ^ Griffiths, A. J. F.; Miller J. H.; Suzuzi D.T.; et al. 2000. An Introduction to Genetic Analysis. New York (7 edition)    
  4. ^ Thompson and THompson. 2015. “Chapter 2: Introduction to the human genome.” Genetics in Medicine. Elsevier (8 edition)    
  5. ^ Craig, Nancy; Cohen-Fix, Orna; Green, Rachel; Greider, Carol; Storz, Gisela; Wolberger, Cynthia (2014). Molecular Biology: Principles of Genome Function (2 ed.). United Kingdon: Oxford University Press. p. 285.
  6. ^ Thompson & Thompson. 2015. "Chapter 4: Human Genetic Diversity: Mutation and Polymorphism." Genetics in Medicine. 8 edition    
  7. ^ Thompson and THompson. 2015. “Chapter 5: Principles of Clinical Cytogenetic and Genome Analysis.” Genetics in Medicine. Elsevier (8 edition)    
  8. ^ Samuels, M. E., Friedman, J. M. 2015. “Genetic Mosaics and the Germ Line Lineage.” Genes 6(2): 216-237. doi:10.3390/genes6020216    
  9. ^ Thompson and THompson. 2015. “Chapter 16: Risk Assessment and Genetic Counseling.” Genetics in Medicine. Elsevier (8 edition)    
  10. ^ Nussbaum, Robert L.; McInnes, Roderick R.; Willard, Huntington F. (2016). Thompson & Thompson Genetics in Medicine (8 ed.). ELSEVIER. p. 51.
  11. ^ Kong, A; Frigge, ML; Mason, G; et al. (2012). "Rate of de novo mutations and the importance of father's age to disease risk". Nature. 488: 471-475. {{cite journal}}: Explicit use of et al. in: |last4= (help)
  12. ^ Gardner, RJ (1977). "A new estimate of the achondroplasia mutation rate". Clinical Genetics. 11: 31-38.
  13. ^ Rogozin, I. B., Pavlov, Y. I. 2003. “Theoretical analysis of mutation hotspots and their DNA sequence context specificity.” Reviews in Mutation Research. 544(1): 65-85. doi:10.1016/S1383-5742(03)00032-2
  14. ^ Thompson and THompson. 2015. “Chapter 4: Human Genetic Diversity: Mutation and Polymorphism.” Genetics in Medicine. Elsevier (8 edition)    
  15. ^ Yauk, C. L., et al. 2013. “Approaches for identifying germ cell mutagens: Report of the 2013 IWGT workshop on germ cell assays.” Mutation Research - Genetic Toxicology and Environmental Mutagenesis Volume 783: 36 - 54. doi:10.1016/j.mrgentox.2015.01.008    
  16. ^ Hurst, L. D, Ellegren, H. 1998. “Sex biases in the mutation rate.” Trends in Genetics Volume 14(11): 446-452. doi:10.1016/S0168-9525(98)01577-7    
  17. ^ Crow, J. F. 2000. “The origins, patterns and implications of human spontaneous mutation.” Nature Reviews Genetics 1, 40-47. doi:10.1038/35049558    
  18. ^ Nagaoka, S. I., Hasshold, T. J., Hunt, P. A. 2012. “Human aneuploidy: mechanisms and new insights into an age-old problem. Nature Reviews Genetics 13(7), 493 - 504. doi:  10.1038/nrg3245    
  19. ^ Beal, M. A., Glenn, T. C., Somers, C. M. 2012. “Whole genome sequencing for quantifying germline mutation frequency in humans and model species: Cautious optimism.” Reviews in Mutation Research. 750(2): 96-106. doi:10.1016/j.mrrev.2011.11.002
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