Li Chuanyun's team proposed the "stowaway hypothesis" that new genes unique to humans originated from lncRNA, revealing the molecular basis of "why people are human"

What makes us uniquely human? In recent years, whether the origin of a new gene might serve as the genetic basis for a trait unique to humans that encodes higher human intelligence has become one of
the most fascinating scientific questions.
While new genes have long been thought to be produced primarily through gene duplication, recent studies have found that de novoorigin also plays an important role in the creation of new genes: in this model, new genes emerge from the noncoding regions of the ancestor to form unprecedented coding proteins
。 But how do these genes emerge progressively from noncoding regions? Professor Li Chuanyun's research group from the School of Future Technology of Peking University used the advantages of rhesus monkeys as a human relative species to find that lncRNA may be a precursor to the birth of
new protein-coding genes.
Although the origin and retention of these new genes may be neutral-driven, and the new genes that have been produced already have biological functions, why are new genes functional at the beginning? How is this "what you see is functional" all-or-nothing transformation achieved? In addition, how do these new genes encode traits unique to humans?

On January 2, 2023, Li Chuanyun's team and the team of Professor Hu Baoyang of the Institute of Zoology, Chinese Academy of Sciences, revealed that cis-element-mediated nucleation such as U1 is the core barrier to distinguish mRNA (protein-coding gene product) and lncRNA (non-coding gene transcript), and natural selection maintains the nuclear and qualitative localization boundaries
of the two types of RNA molecules by controlling the mutations that occur on these core elements 。 Occasionally, certain mutations in lncRNA genes can promote the nucleation and translation of these lncRNAs, and only when the translated protein has a new function of adaptation to the species, these mutations are fixed, resulting in an entirely new protein-coding gene: these new genes, like successful "stowaways", successfully cross the boundary between the two classes of molecules due to their new adaptive functions, and thus exhibit "origin is functional" preadaptation
.
Furthermore, the researchers combined a human-derived brain organoid model and a transgenic mouse model to conduct functional studies on a new gene originating from the above pattern, revealing the key role
of this gene in promoting the evolution of human adaptations such as human brain enlargement.

A model of the origin of a "stowaway" with new genes unique to humans

The findings were published
online in the journal Nature Ecology & Evolution in the form of a long article titled "De novo genes with an lncRNA origin encode unique human brain developmental functionality.
" 。 Nature Ecology & Evolution published a review article titled "De novo gene increases brain size," praising it for its pioneering reveal on the role of RNA processing in new gene production gene origination”）
。 On January 5, Science published a review article titled "Human gene linked to bigger brains was born from seemingly useless DNA" and interviewed a number of well-known scholars in the field to interpret
the paper.

In conclusion, the paper clarifies that cis-component-mediated nucleation such as U1 is the core barrier to distinguish mRNA and lncRNA from two types of RNA molecules.
It answers why these new human genes originating from lncRNA exhibit the characteristics of "origin is functional"; For the first time, from the perspective of experimental science, a case of the biological function of the new gene of human denovo in regulating the early development of the human brain was clarified, which provided an important example for understanding the molecular basis of "why people are human"
.

Li Chuanyun's research group has long used the advantages of rhesus macaques as human closely related model animals to carry out genomics and bioinformatics research
.
They have carefully interpreted the monkey genome and transcriptome (Briefings in Bioinformatics, 2021; Molecular Biology and Evolution, 2014, 2016), built an authoritative "one-stop" monkey genome knowledge base RhesusBase (Nucleic Acids Research, 2013), and carried out a series of monkey perspectives.
Exploring the characteristics of human evolution and disease (Genome Biology, 2021; PNAS, 2018; Nature Communications, 2018; Molecular Biology and Evolution, 2015, 2017; PLOS Genetics, 2012, 2014, 2015), laid the foundation
for the successful completion of this work.

Dr.
Annie, a distinguished associate researcher at the School of Future Technology of Peking University, Jie Zhang, a doctoral student, Dr.
Mo Fan, Institute of Zoology, Chinese Academy of Sciences, and Dr.
Luan Xuke (graduated), School of Future Technology, Peking University, are co-first authors
of this paper.
Li Chuanyun and Hu Baoyang are the corresponding authors
of this article.
This research was supported
by the National Key Research and Development Program, the National Natural Science Foundation of China, and the Beijing Brain Science and Brain-like Research Center.