How New Genes Are Born
Summary of the video “New Genes Just Dropped” by Phy The Neutrophil.
New genes arise through multiple mechanisms: duplicating existing genes via polymerase slippage, retrotransposition, or whole-genome duplication; reshuffling genes through fusion, exon shuffling, and transposon domestication; acquiring genes horizontally from viruses or mitochondria; or spontaneously emerging from non-coding DNA. Each pathway offers evolution a different toolkit for innovation.
Gene Duplication: The Foundation
Polymerase Slippage
During DNA replication, the polymerase enzyme can slip and realign, copying or deleting chunks of DNA. While easy to explain, slippage has limited copying capacity and rarely duplicates whole genes in practice.
Retrotransposition
Mature mRNA (with introns already removed) encounters reverse transcriptase, which converts it back to DNA and reinserts it into the genome. The CDC14B retrogene exemplifies this: it originally regulated the cell cycle via microtubules, but after millions of years evolved a new function associating with the endoplasmic reticulum.
Non-Disjunction and Whole-Genome Duplication
Chromosomes fail to separate during cell division, causing one cell to receive double the genetic material. Though usually lethal, if an organism survives, it gains a redundant copy of every gene, supercharging evolution. Humans experienced at least two whole-genome duplication events in our evolutionary history.
Plant Tolerance for Genome Duplication
Plants tolerate whole-genome duplication far better than animals. The fern with the largest known genome weighs 160 billion base pairs and is octoploid (eight copies of each chromosome), vastly exceeding the human genome.
Gene Reshuffling: Mixing and Matching
Gene Fusion and Fission
Replication errors can bring two genes together to form a hybrid gene, or split one gene into two. This creates new combinations of genetic material without requiring duplication.
Exon Shuffling
DNA tangles during replication; when resolved through recombination, exons (protein-coding regions) can be scrambled into new arrangements. This Frankensteins protein parts together, creating novel proteins from existing modules.
Transposable Element Domestication
Transposons (jumping genes) are parasitic DNA segments that insert themselves throughout the genome, often breaking things. Rarely, mutations convert a useless transposon into something useful, and selection pressure fixes it as a real gene. The most famous example: the transposon Tranib became RAG1 and RAG2, the enzymes powering vertebrate adaptive immunity and VDJ recombination.
Horizontal Gene Transfer: Gifts from Outside
Viral Integration
Genes can originate from ancient viral infections. The syncytin gene, crucial for embryonic attachment in primates, was born from a viral infection that targeted primates and was later domesticated into a useful protein.
Endosymbiotic Gene Transfer
Mitochondria were once independent bacteria engulfed by proto-eukaryotes. Over time, mitochondrial genes migrated to the host chromosome. The mitochondrial polymerase gene, which helps mitochondria replicate, now resides in the host genome, making mitochondria completely dependent on the host for replication.
De Novo Gene Birth: From Chaos
Non-Coding DNA as Raw Material
Non-coding DNA is not junk; it regulates transcription, makes functional RNAs, protects chromosomes, and enables exon shuffling. However, large intergenic regions have no known function and show high variability between individuals and species. These regions can, through improbable mutations, acquire the ability to code for protein.
Three Requirements for De Novo Genes
For non-coding DNA to become a protein-coding gene, three elements must align: the DNA must be close to a promoter, the resulting RNA must be stable, and the RNA must contain a start codon in the right position for the ribosome to initiate translation.
The Numbers Game: Long Non-Coding RNA Abundance
For every unique sequence of coding mRNA in humans, there are about three unique sequences of long non-coding RNA. This vast sea of potential sequences provides unlimited raw material for evolution to eventually convert into functional genes.
Random Peptides and Functional Potential
Most random peptides produce non-functional spaghetti-like structures. However, some random sequences do form alpha helices and beta sheets, providing a genuine starting point for evolution. The yeast gene BSC4, involved in DNA repair, was long considered a de novo gene, though recent sequencing databases suggest it may have ancestral origins.
The De Novo Gene Controversy
Nobel laureate François Jacob wrote in 1977 that the probability of a functional protein appearing de novo is practically zero. However, de novo genes do appear to exist. The challenge: as sequencing databases improve, previously orphan genes may reveal ancestral relatives, making it unclear whether genes are truly de novo or simply divergent from unknown ancestors.
New Human Genes: Examples
NOTCH2NL: Brain Development Specialist
Arose from duplication of the NOTCH2 gene. While initially overshadowed by its famous parent, NOTCH2NL specialized in coordinating growth of the brain's prefrontal cortex, a key region for higher cognition.
NSIM: Regulatory Troublemaker
Arose de novo as an antisense counterpart to MCN. NSIM helps regulate neurodevelopment alongside its sibling, but their interaction has been linked to neuroblastoma (brain cancer) development.
Unnamed De Novo Candidate: Alzheimer's Connection
A very young gene with no assigned nickname, this de novo candidate makes a real protein but its function remains unknown. It is upregulated in Alzheimer's disease, though whether it is protective or destructive in this context is still unclear.
Notable quotes
New genes are basically always the results of happy little accidents. — Phy the Neutrophil
All vertebrates owe the existence of the adaptive immune system to a domesticated transposon. — Phy the Neutrophil
You being here is kind of a miracle on top of a miracle. — Phy the Neutrophil