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Thread: Ancient Genomes and TB

  1. #1
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    Ancient Genomes and TB



    See the original paper:

    https://www.cell.com/ajhg/fulltext/S...297(21)00051-3


    "
    Tuberculosis (TB), usually caused by Mycobacterium tuberculosis bacteria, is the first cause of death from an infectious disease at the worldwide scale, yet the mode and tempo of TB pressure on humans remain unknown. The recent discovery that homozygotes for the P1104A polymorphism of TYK2 are at higher risk to develop clinical forms of TB provided the first evidence of a common, monogenic predisposition to TB, offering a unique opportunity to inform on human co-evolution with a deadly pathogen. Here, we investigate the history of human exposure to TB by determining the evolutionary trajectory of the TYK2 P1104A variant in Europe, where TB is considered to be the deadliest documented infectious disease. Leveraging a large dataset of 1,013 ancient human genomes and using an approximate Bayesian computation approach, we find that the P1104A variant originated in the common ancestors of West Eurasians ∼30,000 years ago. Furthermore, we show that, following large-scale population movements of Anatolian Neolithic farmers and Eurasian steppe herders into Europe, P1104A has markedly fluctuated in frequency over the last 10,000 years of European history, with a dramatic decrease in frequency after the Bronze Age. Our analyses indicate that such a frequency drop is attributable to strong negative selection starting ∼2,000 years ago, with a relative fitness reduction on homozygotes of 20%, among the highest in the human genome. Together, our results provide genetic evidence that TB has imposed a heavy burden on European health over the last two millennia."

    The negative selection selection seems that you die too early to procreate. So why did the negative selection only take hold 2000 years ago?

    It's a very confusingly written abstract and paper. The abstract says the negative selection started 2,000 years ago (and in the paper it's tied to the Iron Age and dense populations living in close proximity to animals), but the paper has different dates, i.e. 5,000 years ago for Europe, for example, which would be around the time of the arrival of the Indo-Europeans. Perhaps it was because of more reliance on domesticated animals?

    See article in Science Magazine:
    https://www.sciencemag.org/news/2021/03/how-tuberculosis-reshaped-our-immune-systems

    "Think of humanity’s worst plagues, and the Black Death, the Spanish flu, and COVID-19 all come to mind. Millions have died in those deadly pandemics, but their toll pales in comparison with that of tuberculosis (TB), which has killed more than 1 billion people over the past 2000 years—and still kills 1.5 million people worldwide every year. But how and when TB got to be so deadly has long been a mystery."

    "The researchers found that the P1104A mutation was ancient—they spotted it in DNA from a farmer who lived 8500 years ago in Anatolia (what is now Turkey) and calculated that the mutation arose at least 30,000 years ago. Anatolian farmers and Yamnaya herders spread this gene variant as they moved into Central Europe. By studying changes in the frequency of the variant over time, the researchers estimated that about 3% of the population carried the gene until about 5000 years ago. By the middle of the Bronze Age, about 3000 years ago, 10% of Europeans had the trait. But since then, its frequency plummeted to 2.9%—the same rate as among today’s Europeans."

    "The steep plunge coincides with when TB’s modern variant emerged, according to ancient DNA studies. Quintana-Murci and his team ran computer simulations on how population size and migration influenced the gene’s frequency. They propose that TB killed or seriously sickened one-fifth of those with two copies of the variant, few of whom had offspring who survived after the end of the Bronze Age, 2000 years ago. As a result, natural selection acted strongly and quickly to weed out the deadly gene variant to low levels, the researchers report today in The American Journal of Human Genetics."

    "The earliest evidence of TB comes from skeletons buried in the Middle East 9000 years ago, soon after the invention of agriculture. But the variant that kills humans today—Mycobacterium tuberculosis—emerged 2000 years ago, when people lived in denser settlements alongside domesticated animals, often reservoirs for TB."


    If you are on @23andMe
    you want to browse for Rs34536443 and see if you are G (good) or C (not good)

    I'm heterozygous. I knew I would be; actually surprised I'm not CC. My mother's family was riddled with it in the 19th and first half of the 20th century.

    This is part of what infuriates me about illegal immigration; these people are not tested and are responsible for the resurgence in the U.S. The strains are also more resistant to anti-biotics. When we came to this country, the first thing you had to submit as part of your documentation was that you were free of TB.

    Not to mention, of course, that they're testing positive for Covid now that the flood gates are open.


    if you are on @23andMe
    you want to browse for Rs34536443 and see if you are G (good) or C (not good)


    Non si fa il proprio dovere perchè qualcuno ci dica grazie, lo si fa per principio, per se stessi, per la propria dignità. Oriana Fallaci

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    1 members found this post helpful.
    Angela: Good informative post, I just checked SNP Rs34536443 and I am GG. Thanks for the cite to the article.

    Last edited by Palermo Trapani; 05-03-21 at 07:40. Reason: additional information

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    1 members found this post helpful.
    Thanks Angela :)

    ... same as PT

    rs34536443 G G


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    Salento: Good deal, that was an informative article Angela posted. There was another article that came out with the Fast Twitch Gene (ACTN3), I was TT on that one, which means non Elite speed Athlete!!!! but apparently good for not being cold. I guess that is why I like my house at about 66 when I sleep but keep it around 68 just to say I am being somewhat energy efficient.

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    Our analyses indicate that such a frequency drop is attributable to strong negative selection starting ∼2,000 years ago, with a relative fitness reduction on homozygotes of 20%, among the highest in the human genome. Together, our results provide genetic evidence that TB has imposed a heavy burden on European health over the last two millennia.

    Do they mean that frequency of
    P1104A dropped because of high mortality caused by TB?

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    According to the NIH website, G allele (TB resistant) is present in 100% of East Asians, 99% of Africans and South Asians, 98.5% of Amerindians, 97.5% of Ashkenazi Jews and 96.5% of Europeans. That would seem to contradict the paper's claim that it spread with West Asian Neolithic farmers and Steppe people.
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    Quote Originally Posted by bicicleur 2 View Post
    Our analyses indicate that such a frequency drop is attributable to strong negative selection starting ∼2,000 years ago, with a relative fitness reduction on homozygotes of 20%, among the highest in the human genome. Together, our results provide genetic evidence that TB has imposed a heavy burden on European health over the last two millennia.

    Do they mean that frequency of
    P1104A dropped because of high mortality caused by TB?
    That's how I interpreted it as well. It makes sense if I'm understanding it correctly that the death rate was particularly high beginning 2000 years ago because there was a new strain present at least in Europe which was particularly lethal.

    It's born out in the literature of, say, the 19th century, when we have more exact descriptions of it and the toll it was taking. They had no idea it was contagious, although they had an inkling that some families were more prone to it. If you were unlucky enough in the roll of the genetic dice to be CC you were done for. Even CG people living in crowded urban settings could get it. It wasn't an old person's disease in most cases. Lots of children and young people died of it, so they often died without having children to spread the C allele presumably.

    There must have been a lot of "C" alleles around in Europe before this purge.

    Heck, where I was born the Bay is called the Bay of the Poets because so many English poets who were tubercular went there thinking the sun and fresh sea air would cure them. That's fine in the summer, but I can't imagine a worse place to be than a poorly heated stone house in the winter months of incessant rain. They should have gone much further south.

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    Vergilius :

    Petit Gemellus nuptias Maronillae et cupit et instat et precatur et donat. Adeone pulchra est? Immo foedius nil est. Quid ergo in illa petitur et placet? Tussit.

    Maronillae was not pretty, but she was rich and she had TB. That's what made her attractive.

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    Thanks Angela

    I am homozygous GG:

    rsid chromosome position genotype
    rs34536443 19 10463118 GG

  10. #10
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    Romans were cynical; French and English writers of the 19th century were romanticists.

    In the 19th century there was quite a cult of the beauty and allure of the pale, languid woman with a flush on her cheeks (caused by high fever), lying on a divan delicately coughing into a handkerchief and then passing away from "consumption", a la "Camille in la dame aux Camelias", by Alexandre Dumas, fils. Being French, she was of course also a courtesan. I think it could fairly be said the French write more about the good hearted, self-sacrificing, beautiful prostitute than any other country, although Italians may come in a close second.:)

    It went from novel to play to film to ballet.





    Indeed, you can't read a Victorian novel without reading about people dying from a disease of the lungs, or returning from a sanitoria in the mountains. The poor, of course, just died.

    The famous Bronte family of English literature fame (Emily, Charlotte, and Anne) were particularly hard hit. Each and every one of the siblings died of it eventually, Mary and Elizabeth as young girls at boarding school.

    "
    • Tuberculosis, which afflicted Maria and Elizabeth in 1825, was the eventual cause of death of the surviving Brontës: Branwell in September 1848, Emily in December 1848, Anne five months later in May 1849, and finally Charlotte in 1855."


    In the incredibly affecting scenes in Charlotte's in describing the illness and death of her friend at boarding school she is describing what happened to her two sisters. Also, in Emily's Wuthering Heights, it is tuberculosis which kills Cathy, the beloved of Heathcliffe."



    It has been a film over and over and over again, most lately, I think, with Hardy in the lead.

    How Tuberculosis symptoms became ideals of beauty:
    https://www.youtube.com/watch?v=Cwo0C0tmCvw

    They were teaching this in university English courses on Victorian literature a couple of decades ago.

    "Day explores the evolution of the scientific understanding of tuberculosis, along with its influence on beauty. She concentrates on the years between 1780 and 1850, when at its peak tuberculosis caused around 25 percent of deaths in Europe, even as it was glamorized.It helped that the wasting away of tuberculosis sufferers aligned with existing ideas of attractiveness. The thinness, the ghostly pallor that brought out the veins, the rosy cheeks, sparkling eyes, and red lips (really signs of a constant low-grade fever), were both the ideals of beauty for a proper lady, and the appearance of a consumptive on their deathbed. If you didn’t have the disease, you could use makeup to get the pale skin and crimson lips, and wear a dress that slumped your posture. Other major diseases of the day, like smallpox and cholera, could be much more gruesome and disfiguring, and were not depicted as gently.
    Art and literature affirmed this perception. The 1850s opera La Traviata, had as its protagonist the consumptive Violetta, inspired by the French courtesan Marie Duplessis, who died of tuberculosis in 1847 at the age of 23. The young diarist Emily Shore, who died at the age of 19, was portrayed in her bed in an engraving. Beside her is a bird, perhaps signaling that soon her soul will take flight. Fashion plates even shaded in the space between the shoulder blades to give them a desirably bony look.
    Marie Duplessis, who died of tuberculosis at the age of 23 in 1847, in a 19th-century portrait by Édouard Viénot (via

    Famous people who had or died of tuberculosis:
    https://en.wikipedia.org/wiki/List_o...rculosis_cases

    I was aware of the usual ones, of course: Keats, Elizabeth Barret Browning, Chopin, but Andrew Jackson, Monroe, Camus?
    So, some of them escaped until adulthood, although none of them left a lot of progeny.

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