In the writing guide section of this blog there is a page about writing discussions. On that page, I refer to the concept of adding width to your discussion in a PhD thesis and mentioned that I ended up talking about the invasion of India by the Mongols in my PhD thesis (“Laminin alpha3 isoforms in cutaneous biology and genetic skin disease”).
Some people have since asked how I managed to work that in while still staying relevant. So, for your enjoyment, and because we never published this part of the story, I have copied it below. Enjoy.
Linkage analysis of the LOCS patients revealed the majority of the patients to share a common haplotype around the LAMA3 locus, which strongly suggests inheritance of a common founder mutation. Determination of the age of the mutation itself is not directly possible however using a likelihood based approach the age of the allele, and therefore time to most common recent ancestor (TMRCA), can be calculated. Essentially this process is based on determination of the length of shared haplotype between each of the individual members and therefore the interval in which recombination (or allele mutation) has occurred. To fine map the location of these recombination events, additional markers were designed around the LAMA3 locus. Recombination rates per generation for many markers have been calculated and assembled into genetic maps.
The locations for the newly developed markers were calculated based on their physical location between the two closest known markers. Marker mutation rates and allele frequencies within the same ethnic group were also taken into account and gave a final value of ~500 years with a mutation rate of 1.2 x 10-3 mutations/marker/generation (Weber and Wong, 1993). However mutation rates at each individual marker are different and the average rate quoted by Weber may only relate to more commonly mutated, and therefore more useful, markers. Reducing the mutation rate to a more conservative 1 x 10-4 mutations per marker per generation gives a TMRCA of ~600 years (95%CI 400-900). Confidence intervals are necessarily large due to the large number of variables, however, these calculations do provide a measure of relatedness for the families.
The finding that the LOCS mutation has a population carrier frequency of approximately 1 in 100 in the British Punjabi Muslim population makes it tempting to search for a historical event that may have caused a bottleneck in this population, allowing this allele to reach this relatively high level. The populations of India and Pakistan have historically been divided into subpopulations by barriers of geography, language, religion, caste or biraderi (patrilineage), resulting in the generation of multiple genetic isolates and the LOCS syndrome may reflect one such isolate (Bittles et al., 2004; Wang et al., 2000).
An answer from history would be purely speculative, however, there are major events that may explain the expansion of LOCS haplotype. Invasion by Mohammed of Ghor in 1192, brought north India under Muslim rule and mass conversion from Hinduism to the Muslim faith. In 1397, the Mongols under Timur Lang (Tamerlane) invaded the Punjab region and northern India and ravaged the entire region causing the fragmentation of Islamic India and separation from a wider kingdom to individual, isolated, regional control (http://www.interknowledge.com/india/india02.htm: A concise history of India). As part of this invasion, Lahore was sacked by an army commanded by Iskender, Tamerlane’s son. It is possible that the survivors of this devastation may have included the founder of the LOCS haplotype allowing its expansion within a resultant subpopulation. The timing of this Mongol invasion falls nicely into the window suggested by our TMRCA studies. A further conquest in 1526-7 by the Mongol Babur may again have led to a local reduction in population, which through maintenance by social construction, may have increased the LOCS haplotype carrier number.
The identification of the LOCS mutation may have important ramifications with respect to prenatal screening and genetic counselling within this community. One important consideration is the prevalence of consanguineous marriages within the population and the relatively high carrier frequency, which together greatly increases the risk of inheriting LOCS.
Note; I think my writing has improved in the 12 years since I wrote this! Certainly, I would edit it today and add a load more primary data references.
Also note; I am not a historian, and make no claims about the veracity of the historical comments!
And one more note… although I would probably do things a bit differently now, I don’t think this is necessarily out of place within my body of work. If I was examining this thesis, I would enjoy exploring these ideas with the student. During my viva, the three examiners and I had a solid scientific and entertaining chat about this stuff, a few laughs at the change in style, and genuinely my memories of my viva are positive.
Want to know more about laminins? I wrote a lay person summary awhile back; available here.
Interested in LOCS – (laryngo onycho cutaneous syndrome, sometimes known as LOGIC or Shabbir syndrome? The primary data with some of the linkage data that set up this section is here or patients/non geneticists might prefer the NIH site on this genetic disease.