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    Home > Active Ingredient News > Endocrine System > The ancient Black Death still affects the human immune system to this day! Do you know the dark side of genes?

    The ancient Black Death still affects the human immune system to this day! Do you know the dark side of genes?

    • Last Update: 2022-11-04
    • Source: Internet
    • Author: User
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    Infectious diseases are one of the most powerful selective pressures driving human evolution, including one of the largest deaths on record in history, the outbreak of the second plague pandemic, commonly known as the Black Death, which was caused
    by Yersinia pestis.
    The plague even had a devastating impact on the African-Eurasian continent, killing as many as 30-50% of the population, and although centuries have passed, its effects seem to be spreading
    to this day.

    The Black Death left a lasting mark on human genetics and changed the frequency at which our immune systems were shaped, which may not be a good thing
    for humans today.

    Genes that once protected humans from plague are now found to be more susceptible to disease

    To identify genes that may have protected humans from infection and death during the Black Death, researchers from McMeister University, the University of Chicago, and the Pasteur Institute characterized 206 immune-related genes from ancient DNA extracts from two different European populations before, during, and after the Black Death
    .
    Through a series of studies, they found that the protective variant overlapped with alleles associated with increased susceptibility to autoimmune diseases today, providing empirical evidence
    for the role of the Black Death in shaping susceptibility to diseases today.
    The research results, titled "Evolution of immune genes is associated with the Black Death," were published in
    Nature.

    Figure 1 Research results (Source: [1])

    The seven-year study took DNA from three different sets of skeletal remains unearthed in London and Denmark, including Black Death victims, people who died before the Black Death, and people who died 10 to 100 years after the plague, and finally the researchers screened 516 DNA samples
    .
    To detect alleles that may have a protective effect or susceptibility to Y.
    pestis, the researchers searched candidate regions (immune genes and GWAS locus) for variants
    that showed large variations in allele frequency between DNA samples before and after the Black Death.
    Compared with a group of non-immune locus, the immune locus at the high-differentiation site is strongly enriched, suggesting positive selection
    of immune genes.

    Ultimately, the researchers identified four genes that provide protection when pathogens invade the human immune system, and found that some of these alleles are protective and others are susceptible
    .
    The strongest association identified by the researchers was between rs2549794 and ERAP2 expression, where protective alleles were associated
    with a 5-fold increase in ERAP2 expression.
    Finally, experiments found that there is a correlation between ERAP2 and the ability to limit Y.
    pestis infection, indicating that ERAP2 is related to the response to Y.
    pestis infection, which in turn supports the idea that
    the change in the frequency of the ERAP2 allele during the Black Death may be caused by natural selection induced by Y.
    pestis.

    If a person carries two protective ERAP2 alleles, they are 40%-50%
    more likely to survive during the Black Death.
    Because people with two copies of the ERAP2 gene have an immune system that produces more functional proteins, which in turn has a stronger ability to
    recognize infections than people with one copy of the ERAP2 gene.

    But everything has two sides, and the researchers found that the Y.
    pestis' choice of ERAP2 may affect the immune response
    to other pathogens or diseases.
    Selection of favorable ERAP2 variants is a risk factor for Crohn's disease today, while the gene CTLA4 with the rs11571319 genetic variant is associated
    with an increased risk of rheumatoid arthritis and lupus erythematosus.

    In summary, by analyzing the DNA of victims and survivors of the Black Death hundreds of years ago, key genetic differences
    were identified that helped people survive the plague.
    These differences continue to shape today's human immune system, with genes that once protected humans from the Black Death now linked to easier replacement for autoimmune diseases such as Crohn's disease and rheumatoid arthritis
    .

    The two sides of genetic evolution: success is also Xiao He, defeat is also Xiao He!

    The above study analyzes the influence on genes during the occurrence of the Black Death, and this effect is still reflected today, indicating that the selective evolution of genes has two sides
    .

    Coincidentally, a study was published in Nature Reviews Genetics and titled "The transition to modernity and chronic disease: mismatch and natural selection.
    " "The study shows that modernization has brought about a completely different environment from the past, genes that are more compatible with the previous environment, which may not be the same in modern life, and may even make people more susceptible to diseases such as Alzheimer's, cancer and cardiovascular disease
    .
    "

    Figure 2 Research results (Source: [2]) 

    In the process of modernization, there has been a mismatch between human evolutionary capabilities and a rapidly changing environment, which has had a great impact on
    human health.
    Genetic effects of previous evolution, mediated by antagonistic pleiotropic (the reference to genes that can have both beneficial and adverse effects), may now account for a large proportion of the NCD burden, which are currently responsible for more than 63% of the world's deaths
    .

    Williams proposed that aging is caused by a combination of many genes that are pleiopotent, meaning they bring benefits at a young age but pay a price
    in old age.
    Several studies have provided direct and indirect evidence that genes associated with an increased risk of diseases in old age are associated
    with increased adolescent survival, fertility and reproductive success.

    For example, women with BRCA1 and BRCA2 mutations are more fertile, but germline mutations in the BRCA1 and BRCA2 genes account for 1-13% of ovarian cancers and 1-5% of female breast cancers.
    The tumor suppressor protein p53 plays a key role in coordinating cellular responses to DNA damage and maintaining genomic stability, and polymorphisms p53 Pro alleles are associated with increased lifespan, but it is also associated with increased incidence of blastocyst implantation failure and infertility; The APOE gene ε4 allele protects infants' cognitive development and is associated with higher fertility in women, but is also associated with an increased risk of Alzheimer's disease and atherosclerosis later in life; Cardiovascular disease risk alleles under positive selection are associated
    with increased lifetime reproductive success.

    These studies provide the strongest evidence to date that genes with antagonistic pleiotropic properties are naturally selected for reproductive and survival benefits, but now increase the risk of
    noncommunicable diseases.

    Alexandre Courtiol, one of the study authors, said: "Genes are guilty, but waiting for natural selection to adapt future generations to modern environments is inefficient, and a more rational response to the increase in chronic diseases is to change the social environment and lifestyle to be more suitable for us
    .
    " ”

    In the future, larger studies are needed to directly measure genetic variation and selection intensity of traits common to contemporary populations across a range of nutritional, cultural and geographic settings, to further understand the antagonistic pleiotropic effects that contribute to the burden of NCDs, and to provide new clues about disease causes
    , potential therapies and possible side effects of new treatments.

    Resources:

    [1] Klunk J, Vilgalys TP, Demeure CE, et al.
    Evolution of immune genes is associated with the Black Death.
    Nature.
    2022 Oct 19:1–8.
    doi: 10.
    1038/s41586-022-05349-x.
    Epub ahead of print.
    PMID: 36261521; PMCID: PMC9580435.

    [2] Corbett S, Courtiol A, Lummaa V, et al.
    The transition to modernity and chronic disease: mismatch and natural selection.
    Nat Rev Genet.
    2018 Jul; 19(7):419-430.
    doi: 10.
    1038/s41576-018-0012-3.
    PMID: 29743650.

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