Although many human proteins are encoded by gene families, it is important to remember that some human proteins have little or no similarity to any other protein encoded by a functional gene. Examples are readily found in many areas of metabolism including the heme, pentose phosphate, and sialic acid pathways.
The following table describes the linkage relationships for members of some other small, intensively studied gene families. Family members may retain similar function but have different patterns of expression. In other cases, members have distinct functions. The gene numbers are from the reference genome sequence. Variation in gene number among individuals is known for amylase. Pseudogenes are not included in those counts. Note how proteins with exceptional conservation such as actin and calmodulin are encoded by dispersed families.
|Distribution of Gene Families on the Chromosomes|
|Gene family||Gene count||Chromosomes||Additional information|
|Calmodulin||3||2, 14, 19||identical protein sequences, many other related proteins|
|Enolase||3||1, 12, 17|
|Actinins||4||1, 11, 14, 19|
|Notch||4||1, 6, 9, 19||also smaller related protein on chromosome 1|
|Amylase||5||1||cluster spans about 205 kb, also pseudogene|
|G β subunits||5||1, 7, 9, 12, 15|
|Actin||6||1, 2, 7, 10, 15, 17||also highly similar ACTBL2 and many other related proteins|
|Polycomb PCGF||6||2, 4, 10 (3), 17||three genes on chromosome 10 not closely linked|
|Alcohol dehydrogenase||7||4||cluster spans about 365 kb|
|Metallothioneins||11||16||cluster spans about 120 kb, also related genes / pseudogenes|
Even with linked families, certain cases are of special interest. Perhaps the most extreme are the rearranging families that encode the antigen receptors on B cells and T cells. As shown in the following table, while occupying considerable DNA segments, these loci would not rank among the very largest human genes. Also of interest is the presence of trypsin genes in the T-cell receptor β locus. In the table, sizes are rounded to the nearest 0.01 Mb.
|Rearranging Loci in the Immune System|
|T cell α / δ||14||0.93|
|T cell β||7||0.58|
|T cell γ||7||0.13|
|Ig heavy chain||14||1.23|
In other cases, a common carboxy-terminal segment is joined to variable amino-terminal sequences via alternate splicing. Two well-studied cases are protocadherin families and the UGT1 family in xenobiotic metabolism.
It is rare for genes unrelated by sequence but related by function to be clustered. One interesting example is found with functions related to the neurotransmitter acetylcholine.
For additional information on the proteins encoded in the mitochondrial genome, see Oxidative Phosphorylation.
|Related Genes on the X and Y Chromosomes|
|Y / X gene pair||Function||Section|
|AMELY / AMELX||amelogenin||Bone and Related Tissues|
|DDX3Y / DDX3X||helicase||DEAD / H Helicase Family|
|EIF1AY / EIF1AX||initiation factor||Translation Factors|
|NLGN4Y / NLGN4X||neuroligin 4||Neurons|
|PCDH11Y / PCDH11X||protocadherin||Cadherins and Related Proteins|
|RPS4Y1 RPS4Y2 / RPS4X||ribosomal protein||Ribosomes|
|KDM5D / KDM5C||PHD Finger Proteins|
|TBL1Y / TBL1X||WD Repeat Proteins|
|TGIF2LY / TGIF2LX||Homeobox and Related Proteins|
|TMSB4Y / TMSB4X||thymosin β 4||Cytoskeleton|
|USP9Y USP9X||ubiquitin-specific protease||Ubiquitin and Related Protein Modifications|
|UTY / KDM6A (UTX)||Tetratricopeptide Domains|
|VCY family / VCX family||Testes and Sperm|
|ZFY / ZFX||Krüppel-related Zinc Finger Proteins|
The genes listed in the table above may have additional transcripts and isoforms. Not included in the table is the XK gene family, which has members on the X, on the Y, and elsewhere in the genome. CYorf15A and CYorf15B are also related to a gene on the X. The RBMY genes also are related to RBMX. PRKY (related to PRKX) is now considered a pseudogene.
The following figure shows the locations on the X chromosome of the genes from the table of Y / X pairs above. Note how the counterparts of the Y-linked genes are found along the larger X chromosome. The size shown is for the X chromosome. The Y chromosome is 57.8 Mb in length with about half in a single unsequenced block (see section on the chromosomes). The pseudoautosomal regions at the telomeres are labeled PAR below the chromosome. These regions cover about 2% of the X chromosome. Many of the genes shown in the figure are close to the larger PAR at the left end of the X (but note that four of these are from the VCX family). When these locations are compared with the positions of the corresponding genes on the Y chromosome, the gene order is largely scrambled.
In many cases, members of sequence families are more divergent. These families may contain a highly conserved domain or a smaller consensus sequence. In other cases, often in smaller families, the encoded proteins may interact with a common partner or with each other.
Trancription factors can be grouped into families via their conserved domains. Most of these are presented in the chapter on Development. Of note is the very large number of genes with Krüppel-type zinc fingers.
Large gene families often have notable subfamilies. Separating these genes into functional groups is not always straightforward. Examples in other sections include the receptor and nonreceptor protein tyrosine phosphatases and the Ser/Thr and tyrosine protein kinases.
In some cases, conserved residues do vary among family members. One example is seen with ERAS (see Stem Cells and Early Development). Sometimes, mutant alleles of one family member introduce residues seen in wild-type alleles of other family members. This is observed with the MEFV gene (see Tripartite Motif Family).
Another is the group of receptors that use the β subunit of the IL3 receptor (see Interleukins and Their Receptors).
Among metabolic enzymes, the α subunit of succinyl-CoA synthetase interacts with two different β subunits with different nucleotide preferences (see TCA Cycle).
The semaphorins and plexins are families of ligands and receptors that also have some sequence similarity to each other.
Metabolic enzymes are frequently encoded by single-copy genes and have little or no overall sequence similarity to other enzymes. A number of enzymes are encoded by distinct, related genes where one is expressed in muscle and the other in liver. Many examples are found in glycolysis and glycogen metabolism. Other pathways, such as the TCA cycle, generally lack such tissue-specific forms.
Brain and testes have many examples of tissue-specific isoforms of proteins. Some are the products of alternate splicing, whereas others derive from separate genes. NOS1 (brain nitric oxide synthase) is in a gene family with two other members. A number of proteins first identified at synapses have been found to be parts of gene families with members expressed in a variety of tissues.
Both mitochondria and peroxisomes have β-oxidation pathways for fatty acids. Mechanistic and structural differences are seen in the enzymes of these related pathways.
Despite the obvious similarities in function, the cytoplasmic and mitochondrial ribosomal proteins generally share very little sequence similarity. A similar but more complex picture is seen with the cytoplasmic and mitochondrial aminoacyl-tRNA synthetases.
The adenylate and guanylate cyclases are a notable example of a gene family with varying sequence similarity and substrate specificity. Fatty acid synthesis and oxidation provide several examples of gene families that have evolved to handle different chain lengths and other substrate differences.
Many gene families described in the Guide also have pseudogenes in varying numbers. Pseudogenes also are are found where there is a single functional copy. An extreme case involves CYCS (cytochrome c). The following figure shows the locations of the numerous dispersed pseudogenes. Unlike human, mouse has a second functional cytochrome c gene. It is found at a location corresponding to one of the human pseudogenes on chromosome 2.
Families for non-protein-coding RNAs can be quite large with a high fraction of psueodogenes. As seen with the CYCS family above, the family members are dispersed among the chromosomes. The following figure shows the sizes and chromosome assignments for sequences related to the U3 RNA involved in ribosomal RNA processing. Although many of these sequences are close to the size of the full-length U3 RNA, note the large fraction of fragments less than 100 bp in size. For additional examples, see Small RNAs in RNA Processing.
Gene sizes and locations used in the figures were from the NCBI Map Viewer coordinates.
For the figure on U3-related sequences, all repeats with names beginning with U3 mapped onto the reference genome sequence were gathered. A total of 230 segments are shown in the figure with 69 being 100 bp or greater in length.
For the second mouse cytochrome c gene, see GI:6753560.
The table on the rearranging loci of the immune system is adapted from the author's A Short Guide to the Human Genome, published in 2008 by Cold Spring Harbor Laboratory Press. It is based on release 36.2 of the reference human genome sequence rather than release 37.1 used in most of this work.
See also the additional reading for this chapter.