My last post mentioned the possibility of Denisovans being linked to Haplogroup P of the Y chromosome, and the possible presence of haplogroup P in America. I thought that it would be straightforward to associate Denisovans with haplogroup P. But after giving it some thought, it isn't. So I decided to recap and go back to the basics and try to find out if it is feasible to associate Denisovans with any human Y chromosome haplogroup.
Transmission and Mutations of Chromosome Y
Chromosome Y is inherited in a patrilineal manner. All men carry one chromosome X and one chromosome Y, they inherit the X from their mothers and the Y from their fathers. In human beings, carrying a pair of X and Y means you are a man. If you inherit the X from both parents, you are a woman.
Base Pairs
Like all chromosomes, Y is made up of DNA (Deoxyribonucleic acid) a molecule that is made up of two counter-spiraling helicoids (like a winding circular stairway), both strands are made up of sugar-phosphate and are the backbone onto which four different compounds (bases) attach. These are Adenine (A), Cytosine (C), Guanine (G), and Thymine (T); these are the steps of the stairway. The bases bind in a particular way, A with T and G with C.
DNA carries the instructions that the cells can read and use it as a template to build proteins.
The bases are laid down in a certain sequence along the spirals, for instance one strand could have: A T G C C T A G T... and the opposing one would have the complementary bases (a T for every A, a C for each G, and viceversa): T A C G G A T C A...
Each pair of linked bases (the rungs of the stairway) is a base pair, for instance A—T. There are 60 to 300 million base pairs in each of our 46 chromosomes, a total of around 3 billion of them in our genome.
Chromosome Y is the smallest in terms of base pairs: roughly 60 million on average.
Genes
Genes are a specific sequence of aligned base pairs in one chromosome. They are the basic unit of heredity. A gene has the codes required to produce special molecules known as RNA or specific proteins.
When cells replicate, or in the case of our sexual gametes (ovarian eggs and sperm), the chromosomes undergo a process of splitting and the DNA strands unwind and replicate. With 3 billion base pairs, copying the new strands can lead to alterations in the base pairs: mutations.
Some base pairs are lost (deletions) others are copied twice (duplications). This alters the blueprint and may have an impact on how the gene that contains these mutations functions. Mutations can be negative (deleterious), neutral, or even positive. As we will see below, mutations in chromosome Y are problematic, as they accumulate.
Hominin Evolution
Our closest primate relative is the common ancestor that we share with chimpanzees, who lived between 6 and 8 million years ago.
This distant ancestor evolved, through a series of mutations into our homo ancestors: Homo habilis and Homo erectus, and others, reaching the common ancestor of Neanderthals, Denisovans, and Homo sapiens.
The original male hominins living 3 or 4 million years ago, carried certain base pair sequences in their Y chromosomes. We can imagine a small population with a few hundred males sharing identical base pairs (this is of course an over simpification, they differed). These "men" then passed their Y chromosomes with these same sequences to their sons. Some of them probably died in their childhood and did not mate, others only had daughters, so their Y chromosomes were lost, only those who had sons passed them on to the next generation.
Mutations
Each generation went through the same process, but the sequences that were passed on, changed over time as chance and external factoes introduced random mutations in the base pairs of the DNA strands of the Y chromosome.
Below are some of the factors that cause mutations:
- Chance, random mutations.
- Age of conception, those men who reproduce later will have more male germ-cell divisions, and each division entails the risk of a failed copy in the sequence. Formation of sperm (or spermatogenesis) implies constant cellular division over a man's lifespan. Female oocytes that result in eggs are all produced at birth, in one go.
- Methylation, the addition of a methyl group (—CH3) to the DNA strand due to epigenetic (lifestyle or external) factors such as stress, famine, or toxins (alcohol, chemicals, smoking).
- Oxidative stress. Sperm are also modified by inflammation, heat, radiation (cosmic rays) which can produce free radicals which are oxidants and degrade the DNA.
- Inadequate repair systems, although the Y chromosome has limited repair mechanisms as it is mostly non-recombining (it has no partner like the other non-sexual chromosomes and does not recombine with the X chromosome). It has limited ability to fix glitches due to its high content of repeat sequences called palindromes.
Unlike other chromosomes, mutations can't be purged in Y chromosomes, so if they are harmful, they will accumulate and lead to genetic malfunction (sterility, illness, death, stillborn boys, and miscarriages). The chromosome will not work as expected. Mutations can reverse, undoing the original variation, but it is an unusual event.
The hominins evolved, but the basic structure of their Y chromosomes was similar, only the accumulated mutations, those that had allowed viable offspring survived, the others vanished as those who carried them died.
The whole genome is subjected to mutations, the X chromosome, and the other chromosomes, and natural selection acts, promoting the survival of the mutations that provide an advantage to those carrying them. It is possible that certain Y chromosomes, even though they were fit and possibly provided survival benefits, were eclipsed by deleterious mutations in other chromosomes. This led to the loss of many Y chromosome variants that had evolved over millennia.
The image Below shows an extremely oversimplified version of a Y chromosome. The original, ancestral version is (1) it has 50 million base pairs (not shown), but one mutated, say an A for a T (shown with the red band). It survives in the following generation and after many generations during which othe over the years, and today, when we look at the global population and sample the men, we find the variants marked (2) to (8), each one carries the original "red" mutation but have added others, each identified with a different color (blue, black, orange, green, violet, and gray).
Haplogroups
Here is where modern geneticists and anthropologists use their computer software tools, algorithms, and theory to build phylogenetic trees. They choose certain base pair mutations known as SNPs as "markers" that define "haplogroups" that split populations into branches from a main trunk (the basal one). Assuming that there are no back-mutations, and that repeat mutations are extremely uncommon, they propose that each marker (a mutation at a given base pair) that is fixed in a given population arose in a sequential manner.
In the example shown above, the phylogenetic tree would be the one shown below, assuming that mutations accumulate and don't reverse:
Caveats
We could argue that (8) resulted from (4) that lost its "blue" mutation, but as mentioned further up, orthodoxy considers that back mutations are rare so they ignore them. Problems also arise when we ask which mutation came first, (2), (7), or (8) they are all just one mutation away from the ancestral root.
In the real world, this is far more complicated, especially when we sequence the Y-chromosome of Neanderthals and Denisovans, which have degraded, decayed, and are incomplete. The strands of DNA of ancient remains are full of voids, and bases that have switched, or flipped. Comparing them with modern strands is done with software that "matches" them and points out the differences.
Toomas Kivisild (2017) highlights the complexity of analyzing haplogroups in ancient Y-chromosome samples: "it can be challenging to distinguish true mutations from those induced by damage, particularly in case of C to T and G to A substitutions", contamination is another factor, and the errors caused by low quality readings caused by "coverage" (how many sites were measured in a sample for comparison with a reference genome) and "sequencing depth" (how many reads covered the sample). All of them can lead to incorrect branch lengths, tree inferences, and dating.
SNPs
And mutations can appear in markers leading to mistaken identifications, like the ones reported by A.T. Fernandes, R. Goncalves, and A. Brehm (2004), in the Azores, where "It was found that some individuals share the same haplotype but belong to different Y-chromosome haplogroup suggesting that SNP mutations may occur frequently." SNPs are Single Nucleotide Polymorphisms (a switch in one base, like an A for a T). This paper notes that "The human Y-chromosome haplogroups are characterized by several mutations according to the phylogeny and nomenclature proposed by the Y-chromosome Consortium. Haplogroups are considered to be stable due to the very low mutation rate of most binary markers (SNPs), around 10−9 per base per generation, showing evidence of recurrent mutation at only 6 of 240 SNPs." This study involved 240 unrelated men and found "three individuals that share an haplotype with a double duplication suggest[ing] that a recurrent mutation occurred in SNP M78 because the duplication event is rare and it is unlikely to occur twice. For the individuals sharing the same haplotype but belonging to different haplogroups two explanations can be possible: recurrent mutations in several SNP namely in M78 and M81 (E3b1/E3b2) and M172 (J/J*) or several STR mutations may have occurred." So much for haplogroups and the assumptions that they are based on! 6 in 240 may seem a low frequency but it is high, 2.5%.
STR, mentioned above is a Short Tandem Repea, a snip of 2 to 6 base pairs long that is repeated two or more times in a location along the DNA strand.
The Branches of the Haplogroup tree
Another factor to consider when looking at ancient and modern DNA is that a man who died 50,000 years ago shows us a picture of a lineage that stopped accumulating mutations then. During the following 50,000 years all other lineages continued adding mutations to their DNA strands at a rate of 10-9 per base per generation (I am using the SNP haplogroup marker value given above). So assuming generations of 25 years, in 50 ky, there are 2000 generatons, and with 50 million base pairs in a Y chromosome, we can calculate 50 x 106 x 2 x 103 x 10-9 = 100 mutations.
When we look at our last shared common ancestor with the Denisovan group who lived ~550,000 years ago, if we assume no mixing with these people since then. After 500 ky, when we met them again in Asia during the Out of Africa migration, each branch, ours, and theirs would have accumulated an average of 1000 mutations (1000 in 50 million base pairs is a very low proportion: 0.002%). With Neanderthals from who we split later, around 350 kya, and met during our first Out of Africa 150 kya, only 400 mutations would have accumulated during the 200 ky we remained apart.
Intra Homo sapiens comparisons like the ones that compare a modern Chinese or a Native American from the Amazon, with an African San, are comparing lineages that have accumulated mutations since they split, probably 60 ky (Chinese and Amerindian) ago from the African line, accumulating mutations separately since then ~120 mutations in each line. And Native Americans with a 30 ky split from Chinese would have added 60 mutations.
Branch Shortening
Finally, and this will be the subject of my next post, mutations do not accumulate at the same rate. Africans have "shorter branches" on the phylogenetic trees. A paper by Petr et al, (2020) using data from an ancient man found in Siberia, Ust’-Ishim, 45,000 years old and modern humans noticed that the number of mutations from the root of each "branche" that leads to Africans and Non-Africans differed, implying different mutation rates (or, in my opinion, incorrect dating of the root, or fork): "Importantly, we discovered that the branch-lengths in Africans are as much as 13% shorter compared to non-Africans, which is consistent with significant branch length variability discovered in previous studies and suggested to be a result of various demographic and selection processes. Notice how they attempt to explain the issue away with "various" processes.
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