What Genetic Mechanisms Made Human Brains so Large?
It is not a specific gene that makes the human brain so large. It is instead a segment [Olduvai protein domains]] of a specific gene family [NBPF] that is repeated many times in humans when compared to other primates, which seems to have provided a big part of the “trigger” to make human brains larger than other primate brains.
SEQUENCES encoding Olduvai protein domains (formerly DUF1220) (Sikela and van Roy 2017) have undergone a human-specific hyperamplification that represents the largest human-specific increase in copy number of any coding region in the genome (Popesco et al. 2006; O’Bleness et al. 2012). The current human reference genome (hg38) is reported to contain 302 haploid copies (Zimmer and Montgomery 2015), ∼165 of which have been added to the human genome since the Homo/Pan split (O’Bleness et al. 2012). Olduvai sequences are found almost entirely within the NBPF gene family (Vandepoele et al. 2005) and have undergone exceptional amplification exclusively within the primate order, with copy numbers generally decreasing with increasing phylogenetic distance from humans: humans have ∼300 copies, great apes 97–138, monkeys 48–75, and nonprimate mammals 1–8 (Popesco et al. 2006; O’Bleness et al. 2012; Zimmer and Montgomery 2015).
Olduvai copy number increase has been implicated in the evolutionary expansion of the human brain, showing a linear association with brain size, neuron number, and several other brain size-related phenotypes among primate species (Dumas and Sikela 2009; Dumas et al. 2012; Keeney et al. 2014, 2015; Zimmer and Montgomery 2015). Among humans, Olduvai copy number (total or subtype specific) has been linked, in a dosage-dependent manner, to brain size, gray matter volume, and cognitive aptitude in healthy populations (Dumas et al. 2012; Davis et al. 2015b), as well as with brain size pathologies (microcephaly/macrocephaly) (Dumas et al. 2012).
These results suggest that the same driver of genomic instability that allowed the evolutionarily recent, rapid, and extreme human-specific Olduvai expansion remains highly active in the human genome.James Sikela et al “Genetics 2020”
When a gene segment is repeated many times (copy number variant) it requires special techniques to detect and quantify the differences. While those who do not know better may believe that the human genome has “been sequenced” and its secrets revealed, those who do know better understand that the game has just gotten started.
The mechanisms that led to the anomalous human brain size described in the research study linked above, are still in play. This means that the human brain is still evolving in terms of brain size and cognitive ability, among many other traits. For better or for worse.
The process of human brain evolution is complex and multifactorial. But step by step scientists are unraveling the mystery.
The process of evolution and humanisation of the Homo sapiens brain resulted in a unique and distinct organ with the largest relative volume of any animal species. It also permitted structural reorganisation of tissues and circuits in specific segments and regions. These steps explain the remarkable cognitive abilities of modern humans compared not only with other species in our genus, but also with older members of our own species.
Brain evolution required the coexistence of two adaptation mechanisms. The first involves genetic changes that occur at the species level, and the second occurs at the individual level and involves changes in chromatin organisation or epigenetic changes. The genetic mechanisms include: (a) genetic changes in coding regions that lead to changes in the sequence and activity of existing proteins; (b) duplication and deletion of previously existing genes; (c) changes in gene expression through changes in the regulatory sequences of different genes; and (d) synthesis of non-coding RNAs.Neurologia 2018
With such a complex process as human brain evolution and development, many things can go wrong. Here are a few of the many ways that genetic development can take a wrong turn:
Inter-individual differences in brain structure are highly heritable1, but identifying the genes that contribute to brain development is challenging. Genome-wide association studies (GWAS) of brain anatomical structures indicate the influence of many single-nucleotide polymorphisms (SNPs) with small effect sizes2,3, but the links to brain function remain weak. Evidence is emerging that some rare copy number variants (CNVs)—that is, regions of the genome that are either deleted or duplicated—are associated with both substantial brain size and shape differences; for example, the 7q11.234,5, 22q11.26,7, 15q11.28,9,10,11 and 16p11.2 proximal12,13,14 and distal CNVs15. Many of these CNVs also have a wide-ranging phenotypic impact, including poorer cognitive abilities8,16,17,18 and increased risk of neurological or neurodevelopmental disorders. The strong impact of these CNVs on brain structure and behaviour make them valuable for studies of the molecular mechanisms contributing to aberrant human neurodevelopment.
The 1q21.1 distal CNV has a known large effect on head circumference, as evident from a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively19,20,21. This, along with its position in a region that is rich in genes unique to the human lineage (i.e. absent in primates)22,23, makes the 1q21.1 distal CNV particularly interesting for the study of aberrations in human brain structure. However, its relatively low frequency, 1 in ~3400, (deletions) and 1 in 2100 (duplications)8,16, has hampered the study of its effects on brain structure.Nature 2021
The authors in the Nature study above emphasize the neurological and neurodevelopmental disorders that can come about due to “abnormal” copy number variants (CNVs). That is permissible, even in today’s “woke and politically correct” environment in science publishing. What they do not talk about, however, is the potential of these research methods to discover why some breeding populations have exceptionally high cognitive capacities when compared to other breeding populations. That would not be politically correct.
More on the Olduvai domain in the NBPF gene family:
Evolution and comparative genomics
The initial name ‘Neuroblastoma Breakpoint gene Family’ (NBPF) was given because the first identified member of the family was found to be deleted in an individual with neuroblastoma . NBPF gene family members include variable numbers of tandemly repeated DUF1220 domains within their coding sequences. Since the name DUF1220 was initially a working designation assigned by the Pfam database curators, Sikela and van Roy  have proposed to rename the domain Olduvai. The different NBPF core duplicon genes are distributed along chromosome 1 in 16 copies, of which 6 are in tandem and 10 are dispersed . The macaque genome has three copies of NBPF genes, while mice and other mammals have no clear orthologs. A possible ancestral gene is PDE4DIP, which includes a single Olduvai domain . The Olduvai domain copy number has particularly expanded in humans. It increased from a single domain in mouse to 30–35 copies in new and old world monkeys and up to 300 domains in humans . Based on sequence similarity, the domain structure of Olduvai can be divided into six primary subtypes including CON 1, 2 and 3 and HLS 1, 2 and 3 [16, 22, 23]. The comparative analysis of Olduvai-domain-containing NBPF genes in primates has shown that NBPF genes evolve under strong positive selection [13, 16].Briefings in Functional Genomics 2019
Several genes have been found to affect the cognitive capacity of humans. Most of the effects of these genes are thought to be quite small. But some genes have been inserted into non-human species with a possible cognition-enhancing result . I am not saying that you should be worried about a “Planet of the Apes” scenario, but you should always keep your bugout bag ready.
Here is more on the mechanism of CNVs in human brain evolution in ordinary language. Note that what they refer to as DUF 1220, is now referred to as “Olduvai.”
Because they can change so fast, CNVs are a very powerful engine of evolution. They allow a species to adapt to an environment very quickly (in evolutionary terms). Knowing this, scientists have looked into human CNVs to see what’s been changing in us, thinking it might give us clues as to what we’ve had to adapt to and maybe even help us understand how we work. What they found was a library of CNV changes — and one mysterious and enigmatic CNV in particular that may finally explain how the human brain got to be so big….
…The most obvious thing to check first is brain size. And sure enough, this rapid increase in DUF1220 copy number has a very strong correlation with both the overall brain size and cortical neuron count in primates, but not with body size. This became even more interesting when researchers sequenced the Neanderthal. Neanderthals are thought to have had larger brains than modern humans, based on skull size. Coincidentally, they also appear to have had ~300 DUF1220 domains.
So researchers began to look for correlations within the human species, and found some. The number of DUF1220s correlates strongly with “cognitive function” (based on total IQ and mathematical aptitude tests), but also with the severity of autism (though it doesn’t seem to actually cause autism). And now, DUF1220 copy number has been linked to schizophrenia, fueling the idea that autism and schizophrenia are diametrically opposed diseases.
It should be noted, though, that it’s really hard to find the differences in DUF1220 between any two humans, unless the difference is really big. You might not think that, in the age of augmented reality and sex education robots that counting would be cutting-edge technology, but it turns out it is. This is because estimating genetic copy number needs some sort of standard to compare it to, which creates a ratio. So if we’re looking at low copy number genes, we can easily find differences of, say, three vs. six. But the difference between 240 and 250 is much more difficult to see.Inverse 2016
There is a lot going on in these genetic interactions, which can make the difference between normal cognition, augmented cognition, schizophrenia, autism, mental retardation, etc. Simple juxtaposition of genetic elements can make a huge difference:
Interestingly, most of the Olduvai triplets are adjacent to, and transcriptionally coregulated with, three human-specific NOTCH2NL genes that have been shown to promote cortical neurogenesis.Sikela et al 2020
IQ researcher Volkmar Weiss, author of “IQ Means Inequality,” is a proponent of the view that differences in cognitive abilities between breeding populations of humans comes from a few large-impact genetic and/or epigenetic parts of the genome, rather than deriving from thousands of “microgene” differences. Weiss mentions the Olduvai (DUF 1220) CNV as one possible source of inherited differences in cognitive abilities. Time will tell, although researchers will have to take care to look specifically at abnormal conditions such as autism, schizophrenia, and mental retardation.
Once again, the phenomenon discussed above does not arise from a special gene, but rather comes from the distribution and location of specific gene fragments that occur in variable copy numbers with significant differences in number between different species and perhaps between different human breeding populations — besides occurring differently in certain abnormal brain conditions such as autism, schizophrenia, mental retardation, etc.