Denisovan (DNA) introgression has shaped the immune system of present-day Papuans.

[NNadir]

Modern technology has allowed for the genetic mapping of other extinct human species, notably Neanderthals (now fully sequenced in several individuals) and Denisovans. It is now recognized that modern humans are the consequences of interbreeding between these species; people of European extraction are thought to have between 2% and 5% Neanderthal DNA. It now appears that SE Asians have some Denisovan DNA.

Some of this DNA has had phenotypical consequences.

Here is the news feed article that directed me to a discussion of the effects of Denisovan DNA on the immune system of native Papuans:

Denisovan DNA Shaped the Modern Papuan’s Immune System

The full article to which the news item refers is a PLoS Genetics paper and is open sourced: Denisovan introgression has shaped the immune system of present-day Papuans

For convenience, here's an excerpt from the introduction:

Modern humans are known to have interbred with Neanderthals [1], Denisovans [2] and possibly other archaic hominins [3]. While genetically similar populations of Neanderthals are thought to have contributed approximately 2% to non-African genomes, Denisovan introgression has been observed to be more variable [4]. Particularly, Denisovan ancestry accounts for up to 5% of the genomes of the Indigenous peoples of Island Southeast Asia and Australia [4, 5]. In addition, these components exhibit a deep divergence from the reference Altai Denisovan genome, providing strong evidence for the occurrence of multiple Denisovan introgression events across time and space [6, 7].

At the genomic level these introgressed archaic alleles are mostly observed outside protein-coding sequences, distributed over non-functional and regulatory regions [8, 9]. Enhancers, in particular, are amongst the top targeted elements of archaic hominin introgression [10, 11]. Here, archaic alleles are thought to drive phenotypic differences by altering gene pre- and post-transcriptional regulatory processes [11]. Furthermore, both Neanderthal and Denisovan variants seem to preferentially affect enhancers in a tissue-specific manner, with highly pleiotropic elements being depleted of archaic variation [12]. However, beyond general agreement that introgressed archaic DNA has mainly been deleterious and actively removed from coding sequences and conserved non-coding elements [8, 12–14], the actual phenotypic consequences of this variation are not well understood. Several lines of evidence highlight associations between archaic DNA and risk for disease traits, including autoimmune diseases [8, 15, 16], or with traits of possible evolutionary advantage for early non-Africans [17–20]. For example, Neanderthal variants within immune genes and immune-related cis-regulatory elements (CREs) have been associated with differential responses to viral infections among present-day Europeans [21, 22].

Unfortunately, two main factors limit our interpretation of the biology of these alleles. First, we still lack a detailed characterisation of global levels of human genetic diversity, vital to identifying differential archaic hominin contributions across modern populations [23, 24]. Because Denisovan DNA is not present in the genomes of modern Europeans, which make up the vast diversity of biomedical genetics cohorts, it has been impossible to link them to phenotype, unlike segregating Neanderthal variants [16, 25]. Second, and more challenging, most of these alleles lie within non-coding sequences where, despite their acknowledged contributions to human evolutionary history [26, 27], an understanding of their actual biological functions remains elusive.

To gain insights into the consequences of archaic introgression in Papuans, we have analysed a previously published dataset of 56 present-day genomes sampled across the island of New Guinea [6]. By comparing the distribution of archaic single nucleotide polymorphisms (aSNPs) and non-archaic SNPs (naSNPs) segregating within these populations, across multiple genomic elements and cell types, we find that aSNPs are enriched within functional cis-regulatory elements (CREs) and transcribed regions, particularly those active within immune-related cells. We also observe that the presence of archaic alleles within these elements can lead to substantial disruption of transcription factor binding sites (TFBSs), with a consistent Denisovan-specific signal affecting immune-related processes. We finally validate these results through experimental testing of multiple Denisovan aSNPs, and find they are associated with significant transcriptional changes in reporter gene experiments...

Interesting I think.

[Timeflyer]

1. So cool and interesting. Amazing what genetics science reveals about our species' deep history.

[mopinko]

2. i 1st read about this a few yrs ago.

it makes a lot of sense to me. have hi neanderthal dna, and multiple ai’s.
had many viruses, and 6 pregnancies, 1 of which ended w a sorta horrific miscarriage.

went through most of my life not rly sick, but not healthy. then i got west nile in ‘02, and spent yrs going from doc to doc. i clearly had a problem. had an ana pattern that looked like a winning bingo card, but no real help except some symptom relief. shogrens is just 1, which is thankfully taken more seriously these days.

it makes perfect sense to me that viruses and pregnancies ping genes that arent usually active, and that a foreign gene popping up would set off other genes.
and the strong ethnic correlation in some ai’s supports this too.
for a lot of ppl, long covid is a big, fat- i told you so- to the med establishment.

hope this leads to something.

[NNadir]

3. You may be interested in this open sourced paper.

McArthur, E., Rinker, D.C. & Capra, J.A. Quantifying the contribution of Neanderthal introgression to the heritability of complex traits. Nat Commun 12, 4481 (2021).

As I read the paper, many of the potentially maladaptive genes associated with Neanderthal DNA washed out with selection, although obviously not all did.

The chief association that these authors seem to note seems to be skin pigmentation related. I find this interesting because I'll be giving a lecture soon in which I will refer obliquely to NKCX5 gene product, a calcium transporter chiefly involved in skin pigmentation via as a part of melanin synthesis. Europeans have a single nucleotide polymorphism in this gene which is a mutant of an earlier form. It accounts for their/my (mutant) skin color. I thus downloaded the paper your comments inspired me to find. Thanks.

Be healthy, be well.