The status of the human gene catalogue

Abstract

Scientists have been trying to identify every gene in the human genome since the initial draft was published in 2001. In the years since, much progress has been made in identifying protein-coding genes, currently estimated to number fewer than 20,000, with an ever-expanding number of distinct protein-coding isoforms. Here we review the status of the human gene catalogue and the efforts to complete it in recent years. Beside the ongoing annotation of protein-coding genes, their isoforms and pseudogenes, the invention of high-throughput RNA sequencing and other technological breakthroughs have led to a rapid growth in the number of reported non-coding RNA genes. For most of these non-coding RNAs, the functional relevance is currently unclear; we look at recent advances that offer paths forward to identifying their functions and towards eventually completing the human gene catalogue. Finally, we examine the need for a universal annotation standard that includes all medically significant genes and maintains their relationships with different reference genomes for the use of the human gene catalogue in clinical settings.

Figure 1:

A major challenge for gene annotation is how to capture the diversity of gene products and functions. For example, although the vast majority of protein-coding genes occur on distinct transcripts, a small number of bi-cistronic transcripts encode two distinct open reading frames on the same transcript. Similarly, introns within protein-coding genes may host noncoding RNAs, including miRNAs, snoRNAs or lncRNAs, which may regulate the transcriptional activity of the locus, or may have catalytic roles unrelated to the main protein product. Alternate splicing of transcripts may give rise to proteins that enhance or inhibit each other. Transcripts that are truncated and cannot produce functional proteins are targeted for nonsense-mediated decay (NMD). These products, together with ubiquitinated proteins (Ub) or unwanted intronic material are rapidly recycled by cellular lysozomes. Other seemingly nonproductive transcripts may be repurposed as functional ncRNAs.

Figure 2:

predicted and observed human gene counts over time. Counts of protein-coding, pseudogene, and non-coding genes are shown. Time points before 2003 and after 2023 (dashed lines) represent an average of predictions from the literature and extrapolations from this perspective article, respectively. Time points from 2003 to 2023 are based on 20 iterations of the NCBI RefSeq annotation of the human reference genome, including both curated and predicted genes.