Colorectal Cancer

Mutations that occur in genes of ancestors and carried on to progenies, generation after generation is called founder mutations. A single man having certain kind of mutation in gene can pass this to his/her descendant. The mutation can cause any kind of hereditary disease. What is hot-spot spontaneous mutation? The mutations that occur spontaneously at most vulnerable and common sites of gene location are hot-spot mutations. What is the difference between founder and hot-spot mutations?

Founder mutations are different in a way from the spontaneous hot-spot mutations that they are inherited intact from parent to offspring, generation after generation. However, the diseases that occur due to the hot-spot mutations are not necessarily related. Even if same disease occurs in different individuals due to hot-spot mutations then it may happen due to different mutations on same arm of gene but different loci. Hence, the individuals are not related as their genetic make up is totally different.

In founder mutations, mutations occurring in ancestors pass to the progenies in its intact form and hence whoever is the carrier of founder mutation has somewhat related genetic make up. Tracing back human history Founder mutations can be used in discovering and tracing back human history. Founder mutation can be differentiated from hot-spot mutations by comparing the sequence of the remaining chromosome. In founder mutation sequence of the chromosome is inherited intact and remains exactly similar to the ancestors and all carriers who inherited founder mutation must have similar sequence.

While those with hot-spot mutations have different sequence of chromosomes and mutations are spontaneous. Benefits of founder mutation Founder mutations may turn out to be positive and protect the carriers from certain diseases under certain circumstances. For example those who are carriers of hemochromatosis mutation have certain kind of mutation that encodes a protein that enhances iron absorption hence they are protected from iron deficiency anemia. “A founder mutation arises in a single individual whose offspring each have a 50% chance of inheriting the mutation.

The fate of the mutation in the subsequent generations will depend on 2 main factors, namely, selection and chance. If the mutation leads to selective advantage, it may increase in frequency. If it leads to selective disadvantage, eg, reduced reproduction, it may disappear. ” (Lynch et al, 2004) Explain how the age of the mutation and its dispersion route are determined Age of mutations Age of the founder mutation is determined by the length of the haplotype. Haplotype is actually the full length mutated chromosome in original founder gene. It can be distinctively recognized and surrounds the mutation region.

But gradually with time as it is inherited in progenies its size reduces and gets shorter with longer age. By determining the length of the haplotype the age of the mutation can be determined to several years back. In inheritance the founder’s mutated gene during its coupling with the mate’s gene exchange parts and sections. One mutated gene from founder’s chromosome and one normal gene from the mate unite and then exchange parts. The new genetic makeup of the progeny contains only large section of founder’s mutated gene. This length of the haplotype can determine how old the founder’s gene is.

Founder mutation of some disease is very ancient dating back to 100,000 years back. The extensive and long length of mutated gene indicates that founder mutation is quite young and only 70 age ago. Dispersion Route Diseases arising due to founder mutations can be traced back to their origin. For example deafness was traced back to origins from Middle East. It was traced via two routes, of which, one is from Mediterranean coast to Italy and Spain. Discuss the implications of founder mutations for linking ethnicity and disease risk Ethnicity All human beings are related by the inheritance of single genome and belong to single family.

Investigators have found common ancestry for some of those unrelated group. Celts and Basques have also been found to be related via gene similarity. Certain types of diseases and their founder mutated genes are more prevalent in certain regions. For example sickle cell anemia is more common in Africa and Middle East. Disease risk Disease risk lies in the fact that the carriers of single copy of mutated gene are usually more protective than those with normal genes without any mutations. However, those who inherit both copies are at very high risk and suffer from diseases.

Most people who are carriers do not necessarily suffer from the disease. Disease is manifested in those individuals who have two copies of founder mutation gene from each parent. Those who have single copy of mutation gene from one parent are only carriers and disease is not manifested. Tracing of disease of hemochromatosis indicated that all individuals having this disease have identical pattern of DNA on chromosome 6. Sickle cell anemia is a disease that is mostly caused by the founder mutations. In this disease the red blood cells distort, hardens and rupture when pass through tiny vessels and eventually result in anemic blood disorders.

This disease is most common in Africa and regions of Middle East. Today five different haplotypes are identified for sickle cell disease showing that this disease has five different founders as mutations for this disease occurred independently in each one of them. One characteristic of this mutation was that whoever had a single copy of the mutated gene, he could survive malarial infection. However, those with both copies from each parent would manifest the disease and suffer from pain and risk of early death. Computer generated Diagram


Dennis Drayna. Founder Mutations Henry T. Lynch, Stephanie M. Coronel, Ross Okimoto, Heather Hampel, Kevin Sweet, Jane F. Lynch, Ali Barrows, Juul Wijnen, Heleen van der Klift, Patrick Franken, Anja Wagner, Riccardo Fodde, Albert de la Chapelle, A Founder Mutation of the MSH2 Gene and Hereditary Nonpolyposis Colorectal Cancer in the United States. JAMA. 2004;291:718-724. Kirsten N. Kangelaris, Stephen B. Gruber, Clinical Implications of Founder and Recurrent CDH1 Mutations in Hereditary Diffuse Gastric Cancer. JAMA. 2007;297:2410-2411. Published online June 3, 2007 (doi:10. 1001/jama. 297. 21. 2410).

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 …

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