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    abnormalities
    pak The figure above popped up on Twitter to show that even within a socialized medical system, in this case in the United Kingdom and its NHS, ethnic differences in infant mortality remain. But what jumped out at me immediately was the high rate for infants whose mothers were born in Pakistan, as opposed to India and Bangladesh. While the Indians are a relatively middle class community (and a diverse one with that, with a large Punjabi Sikh minority and a secondary migrant populations of East African Indian origin), the Bangladeshis are even poorer than the Pakistanis, in part because they are a predominantly immigrant population (the majority of the Pakistanis in Britain today are not immigrants). In light of other data I’ve seen my immediate thought is that the elevated infant mortality rates among the Pakistani Briton children had to be due to inbreeding because of the more common practice of cousin marriage in this community.

    A little searching resulted in finding the original source of figure, Towards an understanding of variations in infant mortality rates between different ethnic groups in England and Wales. In it there is another figure, and it is clear that the elevated infant mortality among Pakistanis is be attributed to congenital defects, which are almost certainly generally of the recessive variety which get exposed due to cousin marriage. Interestingly, and unfortunately, the Pakistani infant mortality rate is also about double the Bangladeshi rate (though the base rate is much higher as these are developing nations). I assume many would superficially attribute this to greater penetration of NGOs and efficacy of development aid in Bangladesh, but it may just be a function of the difference in inbreeding (India’s rate is somewhat higher than Bangladesh’s, but much lower than Pakistan’s).

    Of course because in the Pakistani culture cousin marriage has become normative, and somehow related to Islam, it can be difficult for British public health officials to broach the issue. Here’s an article from 2011, ‘Bradford is very inbred’: Muslim outrage as professor warns first-cousin marriages increase risk of birth defects:

    Concern about the risks to children from first-cousin marriage has been described as the last great taboo.

    Former environment minister Phil Woolas was rebuked by Downing Street in 2008 for saying British Pakistanis are fuelling rates of birth defects by marrying their cousins, with the spokesman for then prime minister Gordon Brown saying the issue was not one for ministers to comment on.

    Mohammed Saleem Khan, chief executive of the Bradford Council for Mosques, said: ‘It is important to discuss these issues, but I just do not know of any firm evidence backing up Professor Jones’s claims. I think we need more conclusive studies so we can know for certain if there is any genuine risk.

    ‘Marriages between cousins is certainly common within south Asia, but it is becoming less so in Britain and also in Bradford. Islam allows you to marry anyone you want, so in many ways Islam promotes diversity.’

    principlespopulationgenetics I suspect that Mohammed Saleem Khan is ignorant, but saying that there’s no evidence that inbreeding leads to elevated disease risk is classic “denialism.” There’s a whole section on inbreeding in Principles of Population Genetics, the canonical textbook in that field (actually, any text on population genetics has to tackle inbreeding since it is a deviation away from HWE random mating). There’s even a classical equation which predicts the proportion of a recessive disease that is likely to accounted for by the number of offspring of first cousin marriage within the population (the rarer the condition, the more likely inbreeding is the culprit, since rare alleles are more likely to be brought together by marriage between relations than non-relations). So we actually know the outcomes of inbreeding scientifically to a first approximation. Whether we choose to do anything in terms of public health or not (there is a ~5 IQ decrease from expectation for the products of first cousin marriage, or about 1/3 of a standard deviation).

    At heart the issue is ultimately of collective social responsibility on a national level vs. individual choice & subcultural norms. Even with aggressive screening for deleterious alleles it seems unlikely that all of the fitness drag can viably be accounted for without massive preimplantation genetic diagnosis projects. A small number of first cousin marriages is something that society can easily handle in the developed world, but when inbreeding is ubiquitous, in can become the focus of public health, as it has in the Gulf countries, which combine high rates of consanginuity with extensive free health care. In other words, subcultural norms rather than individual choice are really the major dynamic to be worried about, since all things equal the preference for marrying your cousin is not that strong for individuals (to my knowledge Tindr does not have a “match cousins” option).

    Of course it is easy to point fingers when something is not your cultural norm. In the developed West it is normative for educated middle class individuals to delay childbearing, often into one’s 30s (as I did). But, delaying childbearing does have some negative consequences, as we all know anecdotally and statistically. Submitted for your approval, Older fathers’ children have lower evolutionary fitness across four centuries and in four populations:

    Higher paternal age at offspring conception increases de novo genetic mutations (Kong et al., 2012). Based on evolutionary genetic theory we predicted that the offspring of older fathers would be less likely to survive and reproduce, i.e. have lower fitness. In a sibling control study, we find clear support for negative paternal age effects on offspring survival, mating and reproductive success across four large populations with an aggregate N > 1.3 million in main analyses. Compared to a sibling born when the father was 10 years younger, individuals had 4-13% fewer surviving children in the four populations. Three populations were pre-industrial (1670-1850) Western populations and showed a pattern of paternal age effects across the offspring’s lifespan. In 20th-century Sweden, we found no negative paternal age effects on child survival or marriage odds. Effects survived tests for competing explanations, including maternal age and parental loss. To the extent that we succeeded in isolating a mutation-driven effect of paternal age, our results can be understood to show that de novo mutations reduce offspring fitness across populations and time. We can use this understanding to predict the effect of increasingly delayed reproduction on offspring genetic load, mortality and fertility.

     
    • Category: Science • Tags: Inbreeding 
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    1. myb6 says:Show Comment

      Razib,

      I apologize I don’t have the time to read the full study until next week, but one thing that I noticed about prior paternal-age effect studies was that there was very little difference once adjusted for the passage of time, ie the expected number of de novo mutations for my son born in 2035 is very close to my grandson born in 2035. Which then makes me think that a cultural norm of high paternal age isn’t a great factor in long-run mutation accumulation, no?

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      • Replies: @Ruben Arslan
      Some responses: We controlled for passage of time (birth cohort) among other things. Average paternal age is not particularly high nowadays compared to our historical cohorts (people start later, but they stop much earlier too because they have fewer kids).
      We have some speculation on changes in long-run mutation accumulation, but it focuses on selection not increasingly delayed reproduction.
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    2. “there is a ~5 IQ decrease from expectation for the products of first cousin marriage”

      Is this for one-time or repeated first cousin marriage?

      There are some interesting numbers in this study of an Indian Muslim population:

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196914/

      (no idea how well regarded that study is).

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    3. Good argument there for freezing some of your sperm when you’re 22 years old or so, for use if you end up having kids in your late 30s or later.

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      • Replies: @Ruben Arslan
      It's a very small effect and I would advise to consider the possibility that freezing your sperm might also damage it (but I know little about that).
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    4. Vijay says:Show Comment

      “Higher paternal age at offspring conception increases de novo genetic mutations ”

      I want to understand this, from the reference frame of India. Until recently (60s), the Indian families tended to be large with age spread between the first and last born often extending 20+ years. High paternal age at offspring conception did not seem to impact genetic mutations of late born children, whereas it did impact the children when they the first born were conceived later. Are there studies that make this differentiation? I realize that this is not important for the US now, but could help us understand genetic mutation impact on children of older parents.

      Read More
      • Replies: @Ruben Arslan
      Three of the populations that we analysed were pre-industrialisation. One, Québec, also had such large reproductive timespans, see these figures: https://rubenarslan.github.io/paternal_age_fitness/1_compare_descriptives.html#reproductive-timespan
      I'd like to hear more about the evidence that within-family paternal age did not affect mutations in India. It sounds odd to me. We make the differentiation between within-family and between-family effects. The latter effect sizes are not given in the manuscript, but they're in the supplementary website that I linked to.
      Within (the ones we are interested in for mutations) are always negative, between often positive.
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    5. Ruben Arslan says: • WebsiteShow Comment
      @myb6
      Razib,

      I apologize I don't have the time to read the full study until next week, but one thing that I noticed about prior paternal-age effect studies was that there was very little difference once adjusted for the passage of time, ie the expected number of de novo mutations for my son born in 2035 is very close to my grandson born in 2035. Which then makes me think that a cultural norm of high paternal age isn't a great factor in long-run mutation accumulation, no?

      Some responses: We controlled for passage of time (birth cohort) among other things. Average paternal age is not particularly high nowadays compared to our historical cohorts (people start later, but they stop much earlier too because they have fewer kids).
      We have some speculation on changes in long-run mutation accumulation, but it focuses on selection not increasingly delayed reproduction.

      Read More
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    6. @Brett
      Good argument there for freezing some of your sperm when you're 22 years old or so, for use if you end up having kids in your late 30s or later.

      It’s a very small effect and I would advise to consider the possibility that freezing your sperm might also damage it (but I know little about that).

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      • Replies: @omarali50
      There is an excellent review of the effects of cryopreservation on the genomes of sperm as well as oocytes here:

      http://www.ncbi.nlm.nih.gov/pubmed/25519143

      It seems there is some detectable damage to DNA, but it is not clear how significant this is in terms of the future health of successfully fertilized embryos. There just isn't enough data out there yet. So yes, there may well be ill effects of freezing a 20 year old male's sperm that outweigh the benefit of using a young person's sperm instead of a 40 year old's. On the other hand, the effects seem to be mostly related to freezing and thawing, not to the duration of storage. So the risk-benefit calculation may improve as you get older.
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    7. Ruben Arslan says: • WebsiteShow Comment
      @Vijay
      "Higher paternal age at offspring conception increases de novo genetic mutations "

      I want to understand this, from the reference frame of India. Until recently (60s), the Indian families tended to be large with age spread between the first and last born often extending 20+ years. High paternal age at offspring conception did not seem to impact genetic mutations of late born children, whereas it did impact the children when they the first born were conceived later. Are there studies that make this differentiation? I realize that this is not important for the US now, but could help us understand genetic mutation impact on children of older parents.

      Three of the populations that we analysed were pre-industrialisation. One, Québec, also had such large reproductive timespans, see these figures: https://rubenarslan.github.io/paternal_age_fitness/1_compare_descriptives.html#reproductive-timespan
      I’d like to hear more about the evidence that within-family paternal age did not affect mutations in India. It sounds odd to me. We make the differentiation between within-family and between-family effects. The latter effect sizes are not given in the manuscript, but they’re in the supplementary website that I linked to.
      Within (the ones we are interested in for mutations) are always negative, between often positive.

      Read More
      • Replies: @Vijay
      Wow, thanks. This is a new high for this blog; paper authors answering questions. If I had known this I would have been better prepared.


      No, I am unable to quickly locate the infamily paper from India, but it mainly discussed lifesapn and disease burden, and it may precisely match what you were looking for.
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    8. Daniel H says:Show Comment

      Naive question. Can the deleterious effects of long term inbreeding (as seems to be the case with certain Pakistani and Arab populations) be mitigated or reversed with time if the population ceases the inbreeding (while still largely maintaining population cohesion by choosing marriage partners who are not close relations, not relations as we commonly understand the concept), or have these populations damaged themselves irretrievably by the practice?

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    9. Helga Vierich says:Show Comment

      Compare with even more radical inbreeding (Australian rural religious cult group): http://www.independent.co.uk/news/world/australasia/australia-incest-case-filthy-and-severely-deformed-children-found-in-remote-farming-community-after-generations-of-inbreeding-8998115.html

      I am curious too how these levels compare with the estimates made by Kelley Harris and Rasmus Nielsen in a paper that first appeared (pre-publication) last October:

      “….we show that the average Neanderthal would have had at least 40% lower fitness than the average human due to higher levels of inbreeding and an increased mutational load, regardless of the dominance coefficients of new mutations. Using simulations, we show that under the assumption of additive dominance effects, early Neanderthal/human hybrids would have experienced strong negative selection, though not so strong that it would prevent Neanderthal DNA from entering the human population. In fact, the increased mutational load in Neanderthals predicts the observed reduction in Neanderthal introgressed segments around protein coding genes, without any need to invoke epistasis. The simulations also predict that there is a residual Neanderthal derived mutational load in non- African humans, leading to an average fitness reduction of at least 0.5%. Although there has been much previous debate about the effects of the out-of-Africa bottleneck on mutational loads in non-Africans, the significant deleterious effects of Neanderthal introgression have hitherto been left out of this discussion, but might be just as important for understanding fitness differences among human populations..” http://biorxiv.org/content/early/2015/10/31/030387

      A rate of 0.5% seems rather high to me. On the other hand, cross cousin marriage (or uncle-niece marriage) might in fact, over time, remove deleterious alleles from the deme. Could customs of this kind have, over the long run, despite the loss of reproductive fitness, actually be beneficial? For example, might there be lower proportions of deleterious alleles among populations with long standing customary in-breeding, than in populations without such customs?

      I note too that among hunter-gatherers there is a rather low rate of inbreeding: among groups in the Kalahari that I was familiar with, genealogies and interview data indicated that even having a single grandparent in common would eliminate chances of marriage occurring.

      Perhaps there is a correlation between inbreeding and the economic system (property inheritance for example).

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    10. Vijay says:Show Comment
      @Ruben Arslan
      Three of the populations that we analysed were pre-industrialisation. One, Québec, also had such large reproductive timespans, see these figures: https://rubenarslan.github.io/paternal_age_fitness/1_compare_descriptives.html#reproductive-timespan
      I'd like to hear more about the evidence that within-family paternal age did not affect mutations in India. It sounds odd to me. We make the differentiation between within-family and between-family effects. The latter effect sizes are not given in the manuscript, but they're in the supplementary website that I linked to.
      Within (the ones we are interested in for mutations) are always negative, between often positive.

      Wow, thanks. This is a new high for this blog; paper authors answering questions. If I had known this I would have been better prepared.

      No, I am unable to quickly locate the infamily paper from India, but it mainly discussed lifesapn and disease burden, and it may precisely match what you were looking for.

      Read More
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    11. Another surprising feature is the high infant mortality for the children of Caribbean-born mothers. Unless I’m quite mistaken cousin marriage is not part of Caribbean culture, and the Caribbeans in Britain are more affluent than the Pakistanis or Bangladeshis.

      Peter

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    12. This explains pretty much the whole plot of Game of Thrones.

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    13. KMD says:Show Comment

      @prosa123
      Figure 4 suggests that the high infant mortality for the children of Caribbean-born mothers is because of premature births and not congenital anomalies. I’ve no idea why premature births should be a particular problem for that group.
      Readers in the USA might find it interesting to compare all of the UK rates with the USA rates.

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    14. omarali50 says:Show Comment
      @Ruben Arslan
      It's a very small effect and I would advise to consider the possibility that freezing your sperm might also damage it (but I know little about that).

      There is an excellent review of the effects of cryopreservation on the genomes of sperm as well as oocytes here:

      http://www.ncbi.nlm.nih.gov/pubmed/25519143

      It seems there is some detectable damage to DNA, but it is not clear how significant this is in terms of the future health of successfully fertilized embryos. There just isn’t enough data out there yet. So yes, there may well be ill effects of freezing a 20 year old male’s sperm that outweigh the benefit of using a young person’s sperm instead of a 40 year old’s. On the other hand, the effects seem to be mostly related to freezing and thawing, not to the duration of storage. So the risk-benefit calculation may improve as you get older.

      Read More
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    15. TipTipTopKek says: • WebsiteShow Comment

      >Older fathers’ children have lower evolutionary fitness across four centuries and in four populations

      Is that corrected for the age of the mother? I would suspect not, because in most cases the siblings would be born to the same woman. This is a classic confounding variable.

      My suspicion would be that the mother’s age had more to do with this, based on the age of the eggs (aging with the ovaries) vs the age of the sperm (freshly brewed as needed).

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      • Replies: @Megalophias
      "Effects survived tests for competing explanations, including maternal age and parental loss."

      You don't even have to click a link, it's in the abstract in the post.
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    16. @TipTipTopKek
      >Older fathers’ children have lower evolutionary fitness across four centuries and in four populations

      Is that corrected for the age of the mother? I would suspect not, because in most cases the siblings would be born to the same woman. This is a classic confounding variable.

      My suspicion would be that the mother's age had more to do with this, based on the age of the eggs (aging with the ovaries) vs the age of the sperm (freshly brewed as needed).

      “Effects survived tests for competing explanations, including maternal age and parental loss.”

      You don’t even have to click a link, it’s in the abstract in the post.

      Read More
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    17. Anonymous • Disclaimer says:Show Comment

      In the case of Pakistan the study has not controlled for very low vitamin D levels in Pakistani mothers. This is caused by the almost total absence of skin exposure to sunlight as a result of the prevailing Islamic female dress code.

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    18. Sean says:Show Comment

      The was a case a few years ago of a couple of young Pakistanis (whose families were well known in their community to not get on) but when in a call centre in Glasgow they became involved, and for a time there was quite a bit of innuendo after the girl suddenly died on a trip to Pakistan

      http://www.dailyrecord.co.uk/news/scottish-news/secret-bride-sobia-wali-killed-967602#fjT59CRJ06YB411j.97

      Anyway, I’ve read that call centres are revolutionising marriage practices among the middle classes of India, because the young are meeting and choosing partners. I have also read that when to two inbred lines are crossed you get a superior offspring, in the first generation at least . I wonder about Pakistanis and Bangladeshis in call centres ect getting together and maybe having cognitively advantaged offspring.

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      • Replies: @Singh
      Doubt it, India is confused about its identity so prosecutes honor killings.

      The other two don't & India won't soon either.
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    19. @Sean
      The was a case a few years ago of a couple of young Pakistanis (whose families were well known in their community to not get on) but when in a call centre in Glasgow they became involved, and for a time there was quite a bit of innuendo after the girl suddenly died on a trip to Pakistan

      http://www.dailyrecord.co.uk/news/scottish-news/secret-bride-sobia-wali-killed-967602#fjT59CRJ06YB411j.97

      Anyway, I've read that call centres are revolutionising marriage practices among the middle classes of India, because the young are meeting and choosing partners. I have also read that when to two inbred lines are crossed you get a superior offspring, in the first generation at least . I wonder about Pakistanis and Bangladeshis in call centres ect getting together and maybe having cognitively advantaged offspring.

      Doubt it, India is confused about its identity so prosecutes honor killings.

      The other two don’t & India won’t soon either.

      Read More
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    20. I estimated a while back that the risk of birth defects for a first birth to a mother over 35 years old is about the same as if she had married her half-brother at age 20.

      Can anybody refute or back that up?

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