The Black Death still affects the human immune system today! Do you know the dark side of genes?

The evolution of living systems never stops, and the emergence of new things is always accompanied by the withdrawal of old things, or even the disappearance of old things, and genes are exactly that
.
And everything has two sides, and the evolution of genes is not exempt from stereotypes
.
Recently, researchers from McMaster University, the University of Chicago, the Institut Pasteur and others have studied the genes that once protected humans from the Black Death, and found that these genes are now associated with
increased susceptibility to autoimmune diseases such as Crohn's disease and rheumatoid arthritis.
That is, the evolution of genes does not always move towards the favorable side, which has two sides
.

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 effect on the Afro-Eurasian continent, killing as many as 30-50% of the population, and although centuries have passed, its effects still seem to be spreading
today.

The Black Death left a lasting mark on human genetics, changing the frequency with which our immune systems are shaped, and perhaps not a good thing
for humans today.

Genes that protected humans from plague,

Nowadays, it is found to make people more susceptible to disease

To identify genes that might protect humans from infection and death during the Black Death, researchers from McMaister University, the University of Chicago, and the Institut Pasteur characterized immune-related genes from 206 ancient DNA extracts from two different European populations before, during, and after the Black Death
.
Through a series of studies, they found that protective variants overlap alleles associated with increased susceptibility to today's autoimmune diseases, providing empirical evidence
for the role of the Black Death in shaping susceptibility to diseases today.
The research results were published in Nature under the title "Evolution of immune genes is associated with the Black Death
".

The seven-year study took DNA extracted from three different sets of skeletal remains unearthed in London and Denmark, including victims of the Black Death, 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 or susceptibility to Y.
pestis, the researchers searched candidate regions (immune genes and GWAS loci) for variants
that showed large changes in allele frequencies between DNA samples before and after the Black Death.
Compared with a group of non-immune loci, the immunoloci of the high-differentiation site are strongly enriched, suggesting positive selection
of immune genes.

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

If a person carries two protective ERAP2 alleles, their likelihood of surviving during the Black Death increases by 40%-50%.

Because people with two copies of the ERAP2 gene can produce more functional proteins, their immune systems are stronger than people with one copy of the ERAP2 gene to
recognize infections.

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

Taken together, analysis of the DNA of Black Death victims and survivors dating back hundreds of years identified key genetic differences
that helped people survive the plague.
These differences continue to shape today's human immune system, and genes that once protected humans from the Black Death are now linked
to easier exposure to autoimmune diseases such as Crohn's disease and rheumatoid arthritis.

The two-sided nature of gene evolution:

Success is also Xiao He, defeat is also Xiao He!

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

Similarly, a study published in Nature Reviews Genetics titled "The transition to modernity and chronic disease: mismatch and natural selection" suggests that modernization has brought about a gene that is completely different from the environment of the past, and has a higher adaptability to the previous environment, which is not necessarily the same in modern life.
It may even make people more susceptible to diseases such as Alzheimer's, cancer, and cardiovascular disease
.

In the process of modernization, there is a mismatch between the ability of human evolution and the rapidly changing environment, which has a great impact
on human health.
Previously evolved genetic effects mediated by antagonistic pleiotropy (defined genes that can have both favorable and adverse effects) may now account for a large portion of the burden of NCDs, which currently account for more than 63% of the world's deaths
.

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

For example, women with BRCA1 and BRCA2 mutations have stronger fertility, but germline mutations in BRCA1 and BRCA2 genes account for 1-13% of ovarian cancer and 1-5% of female breast cancer.
The tumor suppressor protein p53 plays a key role in coordinating cell responses to DNA damage and maintaining genomic stability, and the polymorphism p53 Pro allele is associated with increased lifespan, but it is also associated with increased incidence of blastocyst implantation failure and infertility; The APOE gene ε4 allele protects the cognitive development of infants 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 pleiotropy, subject to natural selection due to reproductive and survival benefits, now increase the risk of
NCDs.

Alexandre Courtiol, one of the study's authors, said: "Genes are sinful, but waiting for natural selection to adapt offspring to a modern environment is inefficient, and a more reasonable response to the increase in chronic diseases is to make the social environment and lifestyle more suitable for us
.
" ”

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