A pseudogene is a broken gene that cannot produce a functional RNA. They are called "pseudogenes" because they resemble active genes but carry mutations that have rendered them nonfunctional. The human genome contains about 14,000 pseudogenes related to protein-coding genes according to the latest Ensembl Genome Reference Consortium Human Genome build [GRCh38.p3]. There's some controversy over the exact number but it's certainly in that ballpark.1
The GENCODE Pseudogene Resource is the annotated database used by Ensembl and ENCODE (Pei et al. 2012).
There are an unknown number of pseudogenes derived from genes for noncoding functional RNAs. These pseudogenes are more difficult to recognize but some of them are present in huge numbers of copies. The Alu elements in the human genome are derived from 7SL RNA and there are similar elements in the mouse genome that are derived from tRNA genes.
There are three main classes of pseudogenes and one important subclass. The categories apply to pseudogenes derived from protein-coding genes and to those derived from genes that specify functional noncoding RNAs. I'm going to describe each of the categories in separate posts. I'll mostly describe them using a protein-coding gene as the parent.
1. Processed pseudogenes [Processed pseudogenes ]
2. Duplicated pseudogenes [Duplicated pseudogenes ]
3. Unitary pseudogenes
4. subclass: Polymorphic pseudogenes
There are many scientists who think that pseudogenes aren't pseudogenes at all—they think pseudogenes are actually genes with a function that's different from the parent gene. These scientists are not kooks,2 in many cases they are very good scientists. Some of them, like Mark Gerstein and his colleagues, merely raise doubts about whether pseudogenes are junk DNA.
Pseudogenes have long been considered as nonfunctional genomic sequences. However, recent evidence suggests that many of them might have some form of biological activity, and the possibility of functionality has increased interest in their accurate annotation and integration with functional genomic data.Other scientists are writing scientific papers that are much more sensationalist ...
Pei et al. (2012)
Abstract: A paradigm shift is sweeping modern day molecular biology following the realisation that large amounts of “junk” DNA”, thought initially to be evolutionary remnants, may actually be functional. Several recent studies support a functional role for pseudogene-expressed non-coding RNAs in regulating their protein-coding counterparts. Several hundreds of pseudogenes have been reported as transcribed into RNA in a large variety of tissues and tumours. Most studies have focused on pseudogenes expressed in the sense direction, but some reports suggest that pseudogenes can also be transcribed as antisense RNAs (asRNAs). A few examples of key regulatory genes, such as PTEN and OCT4, have in fact been reported to be under the regulation of pseudogene-expressed asRNAs. Here, we review what are known about pseudogene expressed non-coding RNA mediated gene regulation and their roles in the control of epigenetic states.
Groen et al. (2014)
Abstract: Pseudogenes have long been labeled as “junk” DNA, failed copies of genes that arise during the evolution of genomes. However, recent results are challenging this moniker; indeed, some pseudogenes appear to harbor the potential to regulate their protein-coding cousins. Far from being silent relics, many pseudogenes are transcribed into RNA, some exhibiting a tissue-specific pattern of activation. Pseudogene transcripts can be processed into short interfering RNAs that regulate coding genes through the RNAi pathway. In another remarkable discovery, it has been shown that pseudogenes are capable of regulating tumor suppressors and oncogenes by acting as microRNA decoys. The finding that pseudogenes are often deregulated during cancer progression warrants further investigation into the true extent of pseudogene function. In this review, we describe the ways in which pseudogenes exert their effect on coding genes and explore the role of pseudogenes in the increasingly complex web of noncoding RNA that contributes to normal cellular regulation.There are even some well-respected evolutionary biogists who question the functionality of "pseudogenes."
Pink et al. (2011)
Pseudogenes: Are They “Junk” or Functional DNA?Given this very public controversy in the scientic literature, it should come as no suprise that the popular press has turned this into a big deal by questioning junk DNA. It should also come as no suprise that anti-science writers gleefully report this "paradigm shift" as evidence for creationism.
Abstract: Pseudogenes have been defined as nonfunctional sequences of genomic DNA originally derived from functional genes. It is therefore assumed that all pseudogene mutations are selectively neutral and have equal probability to become fixed in the population. Rather, pseudogenes that have been suitably investigated often exhibit functional roles, such as gene expression, gene regulation, generation of genetic (antibody, antigenic, and other) diversity. Pseudogenes are involved in gene conversion or recombination with functional genes. Pseudogenes exhibit evolutionary conservation of gene sequence, reduced nucleotide variability, excess synonymous over nonsynonymous nucleotide polymorphism, and other features that are expected in genes or DNA sequences that have functional roles. We first review the Drosophila literature and then extend the discussion to the various functional features identified in the pseudogenes of other organisms. A pseudogene that has arisen by duplication or retroposition may, at first, not be subject to natural selection if the source gene remains functional. Mutant alleles that incorporate new functions may, nevertheless, be favored by natural selection and will have enhanced probability of becoming fixed in the population. We agree with the proposal that pseudogenes be considered as potogenes, i.e., DNA sequences with a potentiality for becoming new genes.
Balakirev and Ayala (2003)
Pseudogenes are not pseudo any more
Abstract: Recent significant progress toward understanding the function of pseudogenes in protozoa (Trypanosoma brucei), metazoa (mouse) and plants, make it pertinent to provide a brief overview on what has been learned about this fascinating subject. We discuss the regulatory mechanisms of pseudogenes at the post-transcriptional level and advance new ideas toward understanding the evolution of these, sometimes called “garbage genes” or “junk DNA,” seeking to stimulate the interest of scientists and additional research on the subject. We hope this point-of-view can be helpful to scientists working or seeking to work on these and related issues.
Wen et al. (2012)
The truth is that the vast majority of pseudogenes are, in fact, pseudogenes. They are junk DNA. A very small number have secondarily acquired a new function. This has been known for decades and the classice examples are in all the textbooks.
Just because a few pseudogenes in different species have a function does not mean that most of them do.
Let's learn about pseudogenes so we can be better informed about this controversy.
1. Pseudogenes will gradually accumulate mutations so that after millions of years ancient pseudogenes can no longer be recognized as pseudogenes. Different computer algorithms have different cut-offs when determining whether something is a pseudogene or not. This is not the only problem.
2. At least not all of them are kooks. Some of them are kooks.
Balakirev, E.S., and Ayala, F.J. (2003) DNA polymorphism in the β-esterase gene cluster of Drosophila melanogaster. Genetics, 164(2), 533-544. [doi: 10.1146/annurev.genet.37.040103.103949]
Groen, J.N., Capraro, D., and Morris, K.V. (2014) The emerging role of pseudogene expressed non-coding RNAs in cellular functions. The international journal of biochemistry & cell biology, 54:350-355. [doi:10.1016/j.biocel.2014.05.008]
Pei, B., Sisu, C., Frankish, A., Howald, C., Habegger, L., Mu, X.J., Harte, R., Balasubramanian, S., Tanzer, A., and Diekhans, M. (2012) The GENCODE pseudogene resource. Genome Biol. 13:R51. [doi: 10.1186/gb-2012-13-9-r51]
Pink, R.C., Wicks, K., Caley, D.P., Punch, E.K., Jacobs, L., and Carter, D.R.F. (2011) Pseudogenes: pseudo-functional or key regulators in health and disease? RNA, 17:792-798. [doi: 10.1261/rna.2658311]
Wen, Y.-Z., Zheng, L.L., Qu, L.-H., Ayala, F.J., and Lun, Z.-R. (2012) Pseudogenes are not pseudo any more. RNA biology 9:27-32. [doi: 10.4161/rna.9.1.18277]