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DNA: Genotypes and Phenotypes

DNA: Genotypes and Phenotypes

While much of the genetic diversity discussed above came from inactive, noncoding, or otherwise evolutionarily neutral segments of the genome, there are many sites that show clear evidence of selective pressure on the variations between modern humans and Neanderthals. Researchers found 78 loci at which Neanderthals had an ancestral state and modern humans had a newer, derived state (Green et al 2010). Five of these genes had more than one sequence change that affected the protein structure. These proteins include SPAG17, which is involved in the movement of sperm, PCD16, which may be involved in wound healing, TTF1, which is involved in ribosomal gene transcription, and RPTN, which is found in the skin, hair and sweat glands. Other changes may not alter the sequence of the gene itself, but alter the factors that control that gene’s replication in the cell, changing its expression secondarily.

This tells us that these traits were selected for in the evolution of modern humans and were possibly selected against in Neanderthals. Though some of the genomic areas that may have been positively selected for in modern humans may have coded for structural or regulatory regions, others may have been associated with energy metabolism, cognitive development, and the morphology of the head and upper body. These are just a few of the areas where we have non-genetic evidence of differentiation between modern humans and Neanderthals.

While the study of DNA reveals aspects of relatedness and lineage, its primary function is, of course, to control the production of proteins that regulate an organism’s biology. Each gene may have a variety of genotypes, which are the variances that can occur within the site of a particular gene. Each genotype codes for a respective phenotype, which is the physical expression of that gene. When we study Neanderthal DNA, we can examine the genotypes at loci of known function and can infer what phenotype the Neanderthal’s mutations may have expressed in life. Below, explore several examples of Neanderthal genes and the possible phenotypes that they would have displayed.

Red-Headed Neanderthals

Ancient DNA has been used to show aspects of Neanderthal appearance. A fragment of the gene for the melanocortin 1 receptor (MRC1) was sequenced using DNA from two Neanderthal specimens from Spain and Italy: El Sidrón 1252 and Monte Lessini (Lalueza-Fox et al. 2007). MCR1 is a receptor gene that controls the production of melanin, the protein responsible for pigmentation of the hair and skin. Neanderthals had a mutation in this receptor gene which changed an amino acid, making the resulting protein less efficient and likely creating a phenotype of red hair and pale skin. (The reconstruction below of a male Neanderthal by John Gurche features pale skin, but not red hair) .How do we know what this phenotype would have looked like? Modern humans display similar mutations of MCR1, and people who have two copies of this mutation have red hair and pale skin. However, no modern human has the exact mutation that Neanderthals had, which means that both Neanderthals and humans evolved this phenotype independent of each other.

If modern humans and Neanderthals living in Europe at the same time period both evolved this reduction of pigmentation, it is likely that there was an advantage to this trait. One hypothesis to explain this adaptation’s advantage involves the production of vitamin D. Our bodies primarily synthesize our supply of vitamin D, rather than relying on vitamin D from food sources. Vitamin D is synthesized when the sun’s UV rays penetrate our skin. Darker skin makes it harder for sunlight to penetrate the outermost layers and stimulate the production of vitamin D, and while people living in areas of high sun exposure will still get plenty of vitamin D, people who live far from the equator are not exposed to as much sunlight and need to optimize their exposure to the sun. Therefore, it would be beneficial for populations in colder climates to have paler skin so that they can create enough vitamin D even with less sun exposure.

A reconstruction of a male Neanderthal head by John Gurche


Neanderthals, Language and FOXP2

The FOXP2 gene is involved in speech and language (Lai et al. 2001). Mutations in the FOXP2 gene sequence led to problems with speech, oral and facial muscle control in modern humans. The human FOXP2 gene is on a haplotype that was subject to a strong selective sweep. A haplotype is a set of alleles that are inherited together on the same chromosome, and a selective sweep is a reduction or elimination of variation among the nucleotides near a particular DNA mutation. Modern humans and Neanderthals share two changes in FOXP2 compared with the sequence in chimpanzees (Krause et al. 2007). How did this FOXP2 variant come to be found in both Neanderthals and modern humans? One scenario is that it could have been transferred between species via gene flow. Another possibility is that the derived FOXP2 was present in the ancestor of both modern humans and Neanderthals, and that the gene was so heavily favored that it proliferated in both populations. A third scenario, which the authors think is most likely, is that the changes and selective sweep occurred before the divergence between the populations. While it can be tempting to infer that the presence of the same haplotype in Neanderthals and humans means that Neanderthals had similar complex language capabilities, there is not yet enough evidence for such a conclusion. Neanderthals may also have their own unique derived characteristics in the FOXP2 gene that were not tested for in this study. Genes are just one factor of many in the development of language.


ABO Blood Types and Neanderthals

The gene that produces the ABO blood system is polymorphic in humans, meaning that there are more than two possible expressions of this gene. The genes for both A and B blood types are dominant, and O type is recessive, meaning that people who are type A or B can have genotypes of either AA or AO (or BB and BO) and still be A (or B) blood type, but to have type O blood one must have a genotype of OO. Various selection factors may favor different alleles, leading to the maintenance of distinct blood groups in modern human populations. Though chimpanzees also have different blood groups, they are not the same as human blood types. While the mutation that causes the human B blood group arose around 3.5 Ma, the O group mutation dates to around 1.15 Ma. When scientists tested whether Neanderthals had the O blood group they found that two Neanderthal specimens from Spain probably had the O blood type, though there is the possibility that they were OA or OB (Lalueza-Fox et al. 2008). Though the O allele was likely to have already appeared before the split between humans and Neanderthals, it could also have arisen in the Neanderthal genome via gene flow from modern humans.


Bitter Taste Perception and Neanderthals

The ability to taste bitter substances is controlled by a gene, TAS2R38. Some individuals are able to taste bitter substances, while others have a different version of the gene that does not allow them to taste bitter foods. Possession of two copies of the positive tasting allele gives the individual greater perception of bitter tastes than the heterozygous state in which individuals have one tasting allele and one non-tasting allele. Two copies of a non-tasting allele leads to inability to taste bitter substances.

When scientists sequenced the DNA of a Neanderthal from El Sidrón, Spain, was sequenced for the TAS23R38 gene, they found that this individual was heterozygous and thus was able to perceive bitter taste - although not as strongly as a homozygous individual with two copies of the tasting allele would be able to (Lalueza-Fox et al. 2009). Both of these haplotypes are still present in modern people, and since the Neanderthal sequenced was heterozygous, the two alleles (tasting and non-tasting) were probably both present in the common ancestor of Neanderthals and modern humans. Though chimpanzees also vary in their ability to taste bitterness, their abilities are controlled by different alleles than those found in humans, indicating that non-tasting alleles evolved separately in the hominin lineage.


Microcephalin and Archaic Hominins

The microcephalin gene relates to brain size during development. A mutation in the microcephalin gene, MCPH1, is a common cause of microcephaly. Mutations in microcephalin cause the brain to be 3 to 4 times smaller in size. A variant of MCPH1, haplogroup D, may have been positively selected for in modern humans – and may also have come from an interbreeding event with an archaic population (Evans et al. 2006). All of the haplogroup D variants come from a single copy that appeared in modern humans around 37,000 years ago. However, haplogroup D itself came from a lineage that had diverged from the lineage that led to modern humans around 1.1 million years ago. Although there was speculation that the Neanderthals were the source of the microcephalin haplogroup D (Evans et al. 2006), the Neanderthal DNA recently sequenced does not contain the microcephalin haplogroup D (Green et al. 2010).


Enamel Formation and Dental Morphology

While changes to the genome can directly affect the phenotypes displayed in an organism, altering the timing mechanism of protein production can cause very similar effects. MicroRNA (miRNA) is one such mechanism: a cell uses miRNA to suppress the expression of a gene until that gene becomes necessary. One miRNA can target multiple genes by binding its seed region to messenger RNA that would otherwise have carried that information to the ribosome to be transcribed into proteins, preventing transcription from taking place. In hominins, one particular miRNA called miR-1304 is exhibited in both an ancestral and derived condition. The derived condition has a mutation at the seed region which allows it to target more mRNA segments but less effectively. This means that in the derived state, some genes will be more strongly expressed due to a lack of suppression. One such trait is the production of enamelin and amelotin proteins, both used in dental formation during development. The suppression of production in Neanderthals, and subsequent lack of suppression in modern humans, could be a contributing factor to some of the morphological differences between Neanderthal and modern human dentition.


Immune Response

Research shows that Neanderthal DNA has contributed to our immune systems today. A recent study of the human genome found a surprising incursion of Neanderthal DNA into the modern human genome, specifically within the region that codes for our immune response to pathogens (Dannemann et al 2016). These particular Neanderthal genes would have been useful for the modern humans arriving in Europe whose immune systems had never encountered the pathogens within Europe and would be vulnerable to them, unlike the Neanderthals who had built up generations of resistance against these diseases. When humans and Neanderthals interbred, they passed this genetic resistance to diseases on to their offspring, allowing them a better chance at survival than those without this additional resistance to disease. The evidence of this genetic resistance shows that there have been at least three incursions of nonhuman DNA into the genes for immune response, two coming from Neanderthals and one from our poorly understood cousin species, the Denisovans.


Clotting, Depression, and Allergies

While many of the genes that we retain for generations are either beneficial or neutral, there are some that have become deleterious in our new, modern lives. There are several genes that our Neanderthal relatives have contributed to our genome that were once beneficial in the past but can now cause health-related problems (Simonti et al 2016). One of these genes allows our blood to coagulate, or clot, quickly, a useful adaptation in creatures who were often injured while hunting. However, in modern people who live longer lives, this same trait of quick-clotting blood can cause harmful blood clots to form in the body later in life. Researchers found another gene that can cause depression and other neurological disorders and is triggered by disturbances in circadian rhythms. Since it is unlikely that Neanderthals experienced such disturbances to their natural sleep cycles, they may never have expressed this gene, but in modern humans who can control our climate and for whom our lifestyle often disrupts our circadian rhythms, this gene is expressed more frequently.