March 14, 2009

Decline of inbreeding over time?

Genetic Future points me to a new paper which aims to show that there has been a decrease in consanguinity over the large century or so.

Such an effect may indeed be real, as higher mobility has increased opportunities for mating between individuals from distant locations. However, the paper is completely ignoring an alternative explanation which may contribute, at least in part, to the observed data.

The authors studied the genomes of individuals of different ages for runs of homozygosity (ROH), i.e., continuous regions of DNA where the two strands are identical to each other. Such regions are typical of inbred individuals, who inherit identical big chunks of genetic material from both parents -- these chunks can be traced to recent common ancestors shared by these parents.

They were able to discover that older individuals had more significant ROHs than younger ones. Ergo -according to them- older generations had more inbred individuals than more recent ones: inbreeding has decreased over time.

There is, however, one catch to this whole argument: older individuals (and they tested individuals up to 99 years of age) are not a random sample of their generations: they are the survivors, the people whose genetic makeup allowed them to reach old age.

Is there any reason to think that surviving older people are similar in terms of their ROHs to the now-dead members of their generation? Here are some relevant data:

Increase of homozygosity in centenarians revealed by a new inter-Alu PCR technique
a significant increase in homozygote genotypes frequency was observed in centenarians. These counterintuitive results suggest that increased homozygosity contributes to human longevity.

The Unusual Genetics of Human Longevity

In no species other than humans do cultural, social, and biological factors interact with each other in modulating complex phenotypes. Thus, the identification of genetic factors that affect human longevity is a true challenge. The model of centenarians provides us a unique opportunity to tackle this challenge. In this Perspective, we discuss some recent findings (the impact of geography and demography on the longevity phenotype, the relationship between longevity and homozygosity, the role of the nuclear-mitochondrial genome cross-talk) by which new ideas are suggested, such as the concept of a complex allele timing as a pivotal process in modulating the probability of achieving longevity.

Homozygosity - not always a bad thing
“Longevity seems to be linked to homozygosity,” Passarino says. This may be because certain copies of some genes boost lifespan, and carrying two of them doubles the effect. A number of DNA analyses have located regions of the genome where centenarians show an unusually high level of homozygosity, he says.
The conclusion: inbreeding may have decreased over time, but testing the homozygosity of people who are alive today is no way to demonstrate it. Direct genomic testing of people from 100 years ago seems plausible, and may disclose whether increase of autozygosity with age is due to reduced inbreeding over time, or to increased lifespan of homozygous individuals.

PLoS Genetics doi:10.1371/journal.pgen.1000415

Measures of Autozygosity in Decline: Globalization, Urbanization, and Its Implications for Medical Genetics

Michael A. Nalls et al.


This research investigates the influence of demographic factors on human genetic sub-structure. In our discovery cohort, we show significant demographic trends for decreasing autozygosity associated with population variation in chronological age. Autozygosity, the genomic signature of consanguinity, is identifiable on a genome-wide level as extended tracts of homozygosity. We identified an average of 28.6 tracts of extended homozygosity greater than 1 Mb in length in a representative population of 809 unrelated North Americans of European descent ranging in chronological age from 19–99 years old. These homozygous tracts made up a population average of 42 Mb of the genome corresponding to 1.6% of the entire genome, with each homozygous tract an average of 1.5 Mb in length. Runs of homozygosity are steadily decreasing in size and frequency as time progresses (linear regression, p less than 0.05). We also calculated inbreeding coefficients and showed a significant trend for population-wide increasing heterozygosity outside of linkage disequilibrium. We successfully replicated these associations in a demographically similar cohort comprised of a subgroup of 477 Baltimore Longitudinal Study of Aging participants. We also constructed statistical models showing predicted declining rates of autozygosity spanning the 20th century. These predictive models suggest a 14.0% decrease in the frequency of these runs of homozygosity and a 24.3% decrease in the percent of the genome in runs of homozygosity, as well as a 30.5% decrease in excess homozygosity based on the linkage pruned inbreeding coefficients. The trend for decreasing autozygosity due to panmixia and larger effective population sizes will likely affect the frequency of rare recessive genetic diseases in the future. Autozygosity has declined, and it seems it will continue doing so.



Maju said...

Link is broken.

Anyhow, the caveats you provide seem just inverse, mirrored readings of the same data. Personally I doubt that inbreeding favors longevity at all (why would it?) and therefore it's likely that this study is more realistic than the others: it just reads the data properly.

Are quasi-centenarians a problem? Maybe. But what does the data for average old people of c. 70-85 y.o. (which is the life expectancy in developed countries for males and females respectively)? People in their 70s are not "survivors" but average old people, they should clarify the issue.

Dino Haramis said...

Perhaps inbreeding is indirectly indicating the likelihood that a given person has lived his life in favorable circumstances. He (and his ancestors) having had time to adapt to certain climes, food, etc., closed off in their own little "world."

Jim Bowery said...

I doubt that inbreeding favors longevity at all (why would it?)

There is clear evolutionary pressure for longevity in humans due to the increasing reliance on and cost of learning. Destroying human capital built up over a lifetime can be very costly to fitness (as long as elders are actually helping, rather than competing with, their younger more fertile relatives). Since mutations tend to be loss-of-function at the transcription level, it may be that the most advanced features of longevity are showing up in recessives.

Average Joe said...

Is it possible that inbreeding favors longevity because the offspring are less likely to inherit genetic material from one parent that conflicts with that of the other?

Salsify said...

Inbreeding can produce health extremes, with some offspring being sickly or dying outright, and some having greater than average strength. One advantage of inbreeding is getting rid of lethal recessives, but at some point a good outcross will invigorate the strain.
My family is long-lived, and has many first cousin marriages going back to many generations on Martha's Vineyard.

Roy said...

But what does the data for average old people of c. 70-85 y.o.(.....)?

But what Maju? Your unfinished sentence suggests you haven't thought things surprise there..

Maju said...

But what Maju? Your unfinished sentence suggests you haven't thought things through....

What unfinished sentence? I wrote two well structured paragraphs, starting with capital letter and ending with a period. WTF!

Roy said...

But what does the data for average old people of c. 70-85 y.o.?

WTF Maju! You may be forgiven if English is not your first language, but this sentence is still meaningless in English. What were you attempting to say?

Maju said...

Ah, LOL.

The verb is missing (just noticed now). It shoud be "say" (or maybe "tell"?), so:

"But what does the data *SAY* for average old people of c. 70-85 y.o.?