Uvodnik
https://doi.org/10.21857/ypn4oc4189
Human-specific genetics: new insights and research opportunities into the molecular basis of neurodevelopmental disorders
Martina Rinčić
; School of Medicine University of Zagreb, Croatian Institute for Brain Research
*
* Dopisni autor.
Sažetak
nervous system, affecting cognitive, emotional, and behavioral functions. Their complex etiology
involves a combination of genetic, environmental, and neurobiological factors. Advances in genomics
have identified various genetic alterations, including chromosomal anomalies, copy number variations,
single-nucleotide polymorphisms, and rare de novo mutations, all of which are linked to NDD
pathogenesis. However, despite a strong genetic basis, the causes of many NDD cases remain unknown.
Current research investigates how genetic modifications influence human neurodevelopmental
evolution, shaping our distinct cognitive abilities. NDDs primarily affect functions distinguishing
humans from other species, such as abstract thinking. Given DNA’s role as a cellular blueprint, one
might assume a “more is better” paradigm in human genome complexity. However, genome size alone
does not define cognitive ability; for instance, the fork fern Tmesipteris oblanceolate has a much larger
genome than humans measuring 160.45 Gbp/1C. Instead, evolutionary comparisons with our closest
relatives, primates, offer better insights. Humans and chimpanzees share approximately 96% of their
genomes. Yet, key genomic rearrangements differentiate them, falling into four categories: regions that
rapidly accumulate changes through evolution, regions that have been lost, duplicated regions, and
regions with variable copy numbers in humans.
One striking example of genomic evolution is the duplication of the ARHGAP11B gene, which is
linked to brain expansion. Expressed in ape cerebral organoids, ARHGAP11B increases the number of
basal progenitors to human levels (Fischer et al. 2022).
Earlier research focused on gene gains, assuming evolutionary advantages stemmed from additional
genetic material. However, recent studies highlight the role of gene loss. Human-specific deletions of
conserved elements (hCONDELs), primarily located in noncoding regions, can impact gene expression.
A study identified 10,032 hCONDELs, affecting intergenic (59%) and intronic (35%) regions,
with 800 showing species-specific regulatory activity. Many deletions lead to transcriptional repression
rather than activation. For example, a single-base deletion in LOXL2 removes a repressor binding site,
resulting in increased gene expression in humans compared to chimpanzees. Genome editing confirmed
this by reintroducing the ancestral base, restoring chimpanzee-like expression levels. Single-cell
RNA sequencing further assessed the impact of this human-specific deletion. Edited cells containing
the ancestral sequence showed significantly lower LOXL2 transcription, mirroring chimpanzee profiles.
This regulatory change triggered widespread alterations in gene expression, with 145 genes exhibiting
differential expressions. Gene ontology analysis highlighted processes related to cell migration,
development, myelination, intercellular transport, and synaptic function (Xue et al. 2023)032 humanspecific
conserved deletions (hCONDELs. Another key feature of genome evolution are human-accelerated regions (HARs), which accumulate
changes at an unusually high rate. A well-studied example, HARE5, regulates FZD8, a receptor in
the WNT pathway. HARE5 is expressed earlier and more intensely during human brain development
than in chimpanzees, leading to increased neural progenitor proliferation and larger brain size in
transgenic mice (McLean et al. 2011)”properties”:{“formattedCitation”:”(McLean et al. 2011. Initial
hypotheses suggested that human-specific structural variants (hsSVs) might alter genome folding, leading
to enhancer hijacking—a phenomenon in which conserved enhancers regulate new target genes.
However, recent studies mapping HARs and human-gained enhancers (HGEs) in neural stem cells
indicate that most HARs still regulate the same genes in both species, challenging this hypothesis (Pal
et al. 2025).
Genomic regions with variable copy numbers also contribute to human-specific traits. One such gene,
SRGAP2C, arose from a partial duplication of SRGAP2A. SRGAP2C inhibits SRGAP2A, enhancing
synaptic density in cortical pyramidal neurons, improving cortico-cortical connectivity, refining neuronal
responses, and strengthening cognitive functions in transgenic mice (Schmidt and Polleux 2022).
What are the implications for NDDs? Genetic variations in human-specific regions are linked to
NDDs. Patients with diverse clinical manifestations, such as microcephaly or reduced gyrification,
often exhibit mutations or deletions in genes unique to humans. Traditional sequencing methods initially
identified these changes, but research now incorporates single-cell epigenomic and transcriptomic
comparisons. Brain development involves dynamic gene regulation across diverse cell types, rendering
human brain evolution a complex and intricate process. The extended developmental period, increased
synaptic complexity, and enhanced connectivity of the human brain stem from genomic and epigenomic
modifications. These insights enhance our understanding of both human cognitive evolution
and NDD genetics, informing future research on how our unique genome influences brain function.
Ključne riječi
Hrčak ID:
333467
URI
Datum izdavanja:
25.6.2025.
Posjeta: 472 *