The functional and evolutionary impacts of human-specific deletions in conserved elements.

Area of Science:

• Genomics
• Evolutionary Biology
• Neuroscience

Background:

• Conserved genomic sequences can be disrupted in humans, potentially explaining unique human traits.
• Understanding these disruptions is key to identifying the genetic basis of human evolution.

Purpose of the Study:

• To identify and characterize human-specific conserved deletions (hCONDELs).
• To investigate the functional impact of hCONDELs on gene regulation and human traits, particularly brain development.

Main Methods:

• Identification and characterization of 10,032 hCONDELs from genomic data.
• Analysis of genetic, epigenomic, and transcriptomic datasets for enrichment of brain functions.
• Massively parallel reporter assays in six cell types to assess regulatory activity of hCONDELs.
• Experimental reversion of an hCONDEL to its ancestral sequence to observe gene expression changes.

Main Results:

• Discovered 10,032 hCONDELs, averaging 2.56 base pairs, enriched for brain functions.
• Identified 800 hCONDELs with significant regulatory activity, with half enhancing function.
• Highlighted hCONDELs affecting brain development genes like HDAC5, CPEB4, and PPP2CA.
• Demonstrated that reverting an hCONDEL alters expression of LOXL2 and genes related to myelination and synaptic function.

Conclusions:

• hCONDELs are a significant source of human-specific genetic variation impacting gene regulation.
• These deletions play a role in the evolution of human brain development and function.
• The identified hCONDELs provide a valuable resource for studying human evolution and associated traits.