Defining Founder Mutations

In certain geographically isolated or ethnic populations, particular mutations are found with increased frequency relative to other populations. A common explanation for this is that the population is descended from a relatively small group of individuals, at least one of whom harbored the mutation in question. Thus, the prevalence of the mutation was increased in the gene pool of this group and has been maintained because of breeding within the group. Such a mutation is called a founder mutation and the phenomenon is known as a founder effect (Killeen, 2004 p. 67-68).

Founder mutation has been defined as the disease-causing mutation that is found repeatedly in a given population and is derived from a common ancestor who harbored such genetical alteration. Founder effects are seen both fir dominant and recessive disorders and, if the disorder is due to founder effect, the affected individuals in a given population carry the same mutation. Examples include recessive disorders Meckel syndrome, hydrolethalus syndrome, Cohen syndrome, and Congenital Finnish nephropathy, which all occur with disproportionately high incidence in Finland compared with other European populations (Lalloo, 2005 p. 35).

Founder mutation has been identified in other ethnic subpopulations, including Belgians, German, Latvians, Norwegians, Russians, and Swedes. The presence of recurring mutations, with emerging evidence of founder effects, has also been observed in Asians, which encompasses individuals descended from multiple regions including China, Japan, Philippines, and other areas. Although a few founder mutations have been identified in families of African ancestry, many of the mutations identified in this population are novel (Harris, 2004 p. 325).

The Age of the Mutation and its Dispersion Route The different random mutations cause the mutant copies to have different sequences, which are then cloned and sequenced. Mutations introduced at very early rounds of amplification can establish founder mutations that occur in a significant proportion of the progeny amplimers, although these founder mutations are themselves at random loci. These characteristics allow the influence of founder mutations to be minimized through simple experimental design devices.

The DNA sequences determined from a low number of the altered copies can then analyzed using Bayesian methods to reconstruct the original wild-type sequence (Keith et. al, 2003; cited in Michelson, 2007 p. 309). Surprisingly, this entire process has efficiencies and accuracies roughly equivalent to conventional sequencing (Michelson, 2007 p. 309). As the initial population is quite small, only a handful of copies of a mutation, the founder mutations, may have entered the bottleneck in different founder haplotypes.

The effect of drift is at its strongest during the period of slow growth, skewing the distribution of the founder mutation frequencies. Consequently, only a few of the founder mutations are likely to be present in the current population in significant numbers. Small isolated founder populations such as Kainuu in northeastern Finland or the French Canadians are examples of recent bottlenecks. The Caucasian population is thought to have gone through a bottleneck approximately 50. 000 years ago as they migrated out of Africa (Wang, 2005 p. 107).

Several studies have examined the genetic epidemiology of breast cancer associated to founder mutations; however, founder effects have not been marked as those observed in Ashkenazi Jews and Icelanders, and the population frequency of recurring mutations is largely unknown (Harris, 2004 p. 326). Implications of Founder Mutations The classic example of a founder effect in recent history is hemophilia, the uncontrollable bleeding disease that plagued many of the royal families of Europe and Russia. England’s Queen Victoria was the genetic founder for the disease, since it had never occurred in her ancestors.

However, several of her children and grandchildren developed it and introduced it into the royal families of Europe and Russia. Founder effects arise among small groups of people who have their movements restricted and choose to marry or are forced to marry others from within a small group. This inbreeding maintains the founder mutation in that population. Once the group expands, the founder mutation spreads to a much larger proportion of the population and accounts for the relatively high frequency of certain diseases in those populations.

Because of these founder effects, a very few individuals can have a major impact on a family, as in the case of Queen Victoria, or on a population (Lalloo, 2005 p. 37). Phenylketonuria, for instance, occurs very rarely among Ashkenazi or Sephardic Jews, but has a relatively high frequency among Jews from Yemen. In this latter group, the disorder is caused by a mutation that has been traced to a single Jewish inhabitant of the capital of Yemen in the early 18th century (Michelson, 2007 p. 314).

Founder effects that are dominant” may appear in the founder’s children. If “recessive,” they might not show up for many generations later. Some mutations, on the other hand, have ‘survival value” because they increase resistance to disease; for example, the disorder that causes sickle- cell disease is found in regions with endemic malaria and confers resistance to that disease. Some disorders like Tay-Sachs, Gaucher and Mucolipidosis are due to gene mutations that affect the same internal cellular component, the lysosome (Abel, 2001 p.17).

References Abel, E. L. (2001). Jewish Genetic Disorders: A Layman’s Guide. McFarland. Harris, J. R. (2004). Diseases of the Breast. Lippincott Williams & Williams. Killeen, A. A. (2004). Principles of Molecular Pathology. Humana Press. Lalloo, F. (2005). Risk Assessment and Management in Cancer Genetics. Oxford University Press. Mitchelson, K. R. (2007). New High Throughput Technologies for DNA Sequencing and Genomics. Elsevier. Wang, J. T. (2005). Data Mining in Bioinformatics. Springer.

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