--The gene L-gluonolactone oxidase is required for an organism to synthesize its own vitamin C.  In primates and guinea pigs, this gene lost its function.  Presumably, the ancestral primates ate enough fruits that the inability to synthesize vitamin C was no great disadvantage to them.  Humans still possess a non-functional pseudogene for this enzyme on chromosome 8p21.1 (OMIM).




     The existence of different blood groups in a species seems to be a typical condition of vertebrate groups including sharks, teleosts, birds, and mammals (Hoar, 1983).

     The proteins whose variants result in the Rh blood groups are significant factors in blood transfusions,  the possible maternal immune reaction against fetuses, and even as a potential mechanism for reproductive isolation of different human populations.  Red blood cells can possess an Rh complex on their surface which composed of two Rh proteins, 2 RhAG proteins, the duffy glycoprotein, and several other components.  The blood RH proteins are encoded by two genes RHCE and RHD while other members of the Rh family in humans include RHAG, RHGK, and RHBG genes.  

     Humans express two members of the Rh gene family on red blood cells and 2 on white blood cells.  The gene duplication which resulted in the two genes expressed on red blood cells predated the African ape lineage.  The two proteins expressed on red blood cells produce the D antigen and the other produces the C/c and E/e antigens.  Rh negative individuals lack the gene producing the D antigen.  Rarely, humans without either Rh gene are born but they suffer from anemia.  Rh also expressed in human (and mouse) kidneys, brain, and other tissues (Huang, 2001; Westhoff, 1999).  The Rh protein seems to be a channel which allows the bidirectional transport of carbon dioxide, ammonia gas, NO, and oxygen.  Although the function of these glycoproteins is not entirely known, they are homologous to ammonium transporters in bacteria, fungi, plants, invertebrates, and a number of vertebrates.  Mutations limit the growth of algae in high carbon dioxide concentrations. RhAG and RhGK have been shown to function in ammonium transport (Okuda, 2002; Soupene, 2004).  Rh-like proteins known in nematodes and sponges (Seack, 1997).



     In humans, the blood types A, B, and O are determined by the oligosaccharide groups which are attached to the H antigen.  Although the significance of these sugar groups is not fully known, they are a factor in determining the gastrointestinal diseases a person in most susceptible to.  For example, individuals with the blood type AB are much more resistant to cholera than those with the blood type O.  The genes which determine these blood types are enzymes which transfer sugar units called glycosyltransferases.  Glycosyltransferases are usually classified based on which sugars they transfer.  However, some related genes can perform different transfers.  For example, poly-N-acetyllactosamine synthase is structurally similar to β1,3-galactosyltransferases(Zhou, 1999).  Glycosylation functions in deactivating toxins and the glycosylation of cells affects their tendency to cancer (Zhou, 1999; Wiggins, 1998).


β1,4-galactosyltransferase functions both in the widespread biosynthesis of glycoconjugates and in the synthesis of lactose in active mammary glands.  This enzyme is present in the Golgi of vertebrate cells where it attaches galactose to N acetylglucosamine (Charron, 1998). 


      Plants retain the glycosylation mechanism producing oligosaccharides rich in mannose-type-N glycans found in primitive eukaryotes.  In mammals however, a number of modifications occur, such as the use of galactose and sialic acid residues at the end of oligosaccharides (Palacpac, 1999).




      In order to use lipids for energy, animals needed proteins to carry them in polar solutions.   In vertebrates, ApoA-I is the primary HDL (Babin, 1997).   ApoA-I and ApoE are expressed in yolk sac.  The duplication which produced these two genes from an ancestral gene them predates the evolution of bony fish (Babin, 1997). Apolipoprotein(a) is homologous to plasminogen and the gene possessed by humans is known only in Old World monkeys and apes.  High levels of Apo(a) can interfere with plasminogen activation and increase the risk of heart attack and stroke.  Some insectivores (hedgehogs) possess a Apo(a)-like molecule but it seems to have evolved separately from that found in catarrhine primates (Lawn, 1997)


     Members of the apolipoprotein gene family all bind lipids.  It appears that the ancestor of the apolipoprotein gene family was a small gene which duplicated to form a larger gene with two exons.  These exons fused and were duplicated and a signal peptide domain was added to produce a small apoplipoprotein gene similar to Apoplipoproteins A-II, C-I, C-II, and C-III.  Further amplification occurred within exons and unequal recombination events to produce larger apolipoproteins such as A-I, A-IV, and E.  Humans possess eight members of this gene family (Boguski, 1986; Barker, 1977).

     ApoA-I, ApoC-III, and ApoA-IV genes exist in a cluster on chromosome 11 while ApoE, ApoC-I, and APoC-II exist in a cluster on chromosome 19.  The genes ApoC-I, C-II, CIII qnd A-II, AIV, and A-II appear to belong to a gene family whose members diverged in this order.  If AoB is a member of the apolipoprotein gene family, it has undergone considerable modification.  ApoD is not a member of the same gene family with other apolipoproteins (Li, 1988)


Lamprey lipoprotein is similar to human A-II and C-III. (Li, 1988)


ApoB-100 is made in the liver and forms the part of LDL and VLDL particles which binds the LDL receptor.


ApoB-48 is made in the intestines for chylomicrons.  


ApoE mediates the biding of lipoproteins to LDL receptors and apo-E receptors.


ApoC-II activates the lipase which breaks down chylomicrons and VLDLs.


ApoC-III inhibits the lipase activated by ApoC-II.


ApoA-I activates the enzyme lecithin: cholesterol acyltransferase (LCAT) which acts in the formation of HDL and LDL particles.


ApoA-IV also activates LCAT (Li, 1988)


Apolipophorin II/I, Apolipoprotein B, vitellogenine and microsomal triglyceride transfer protein genes form a fene family.  Vitellogenin is a protein involved in egg formation which is secreted by fat bodies in insects, the intestine in nematodes, and the vertebrate liver (Babin, 1999).


ApoA-I, A-II, E, C-I, C-II, and C-III are members of the same gene family with conserved positions of their three introns.  Duplication  of internal blocks of codons has occurred.  Common ancestor similar to C-I.  the first 11 codons in exon 4 were duplicated after primordial gene duplicated to produce the ancestor of C-1 and the ancestor of all the others.  After another duplication, one was ancestral to C-II and the other duplicated 22 codons of exon 4.  The lineaged leading to A-II and C-III underwent a deletion of 11 codons

While the lineage leading to E, A-IV, and A-I underwent additional duplications (Luo, 1986).



     In individuals affected by microcephaly, the brain may only reach a third of its normal size (about the size of that found in early hominids) and the gyral pattern is less complex than normal.  These individuals have reduced cognitive ability but are otherwise normal.  There are two genes whose mutations are known to cause microcephaly.


Abnormal spindle-like microcephaly associated ASPM is a large protein which interacts with microtubules and is expressed in areas where new neurons are produced.  Its homolog in flies is known to function in the organization of microtubules during cell division (Ponting, 2005).


Microcephalin (MCPH1) is related to topoisomerase II-binding protein and BRCA1.  It regulates chromosome condensation in mitosis and DNA repair.  Homologs exist in bilateran animals (Ponting, 2005).

     In ape lineages, both of these genes have undergone positive selection unlike that of other mammalian lineages, suggesting that they have contributed to brain growth in apes (Ponting, 2005).



     Most vertebrates depend on an exchange between chloride and bicarbonate ions for the carbon dioxide transport of red blood cells.  In jawless fish, this ability is extremely limited.  Unlike lampreys, hagfish red blood cells do not transport additional carbon dioxide in deoxygenated blood compared with oxygenated blood and there is no measurable Haldane effect.   Lungfish blood undergoes a significant Haldane effect while sharks do not (Hoar, 1983).  Hagfish red blood cells have a less significant role in transporting carbon dioxide, accounting for 30% of that which can be lost at the gills as opposed to 65% in lampreys (Tufts, 1998).  The red blood cells of bony fish are evident in the following image.


     Carbonic anhydrase (CA) is an enzyme which converts carbon dioxide and water into carbonic acid which then dissociates to form bicarbonate.  In humans, 70% of the carbon dioxide transport in the blood is in the form of bicarbonate (23% is bound to hemoglobin and 7% is dissolved in solution).  Carbonic anhydrase existed long before vertebrate circulatory systems, given that it is known from bacteria and plants (Hoar, 1983).  The diverse carbonic anhydrase genes in living organisms, including the multiple genes which can be expressed in mammals, belong to one gene family (Tufts, 2003).  Rates of CA activity suggest that there have been increases in the catalytic efficiency of CA in the ancestors of agnathans and in the ancestors of higher vertebrates (Tufts, 2003)..



There are three GnRH genes known which appear to have resulted from an ancestral gene which was duplicated in ancestral vertebrates.  GnRH genes are not part of a larger gene family. Two of the three resulting decapeptides have the same amino acid sequence in all known species.  GnRH3 is known only in fish to date (Fernald, 1999).  In humans, GnRH1 is produced in the spleen, lymphocytes, liver, muscle, kidney, placenta.  Expression is also widespread in fish.  GnRH2 is expressed in the human brain, prostate, bone marrow, and kidney (Fernald, 1999).




 Ubiquitin occurs in all eukaryotic cells and in archaea but is not known from eubacteria. (Gamulin, V., from Muller, 1998.)

    Ubiquitin is found in all eukaryotic cells and is one of the most evolutionarily conserved genes known (it may be the most conserved protein).  The protein sequence is identical in animals ranging from insects to humans.  Plant and yeast versions only differ by three amino acids.  The small ubiquitin protein binds to intracellular proteins so that they can be degraded.  This process requires ATP but not lysosomes.  In the fertilized eggs of monkeys and cows, the mitochondria which originated from the sperm are tagged with ubiquitin and are subsequently degraded.  Abnormal UbiquitinB protein may be involved in neurodegenerative diseases such as Alzheimers disease (OMIM).

     The members of this multigene family exist in a number of forms.  One gene codes for a single ubiquitin protein.  In other genes, there are multiple copies of single ubiquitin sequences arranged in tandem.  After the polyprotein is made (containing 3-4 ubiquitin units or 9 units), it is then broken into the ubiquitin monomers.   Still other ubiquitin sequences have been fused to sequences coding for other, nonrelated proteins.  On fusion protein is broken down in eukaryotic cells to produce ubiquitin and ribosomal protein 27A.  There are also many ubiquitin psedogenes dispersed throughout the human genome (OMIM).



There are a number of unrelated genes which have evolved the ability to degrade RNA. The RNase A gene family seems to be a gene family which evolved in vertebrates and has undergone significant expansion in primates, producing 13-20 members. In the human genome, these genes form a cluster on chromosome 14q11.2. This family has undergone the greatest expansion in opossums producing 21 genes and 3 pseudogenes. At least 3-4 members of the family existed in the common ancestor of placental mammals. It seems that some of the functions performed by these RNases are not essential since ancestral genes have been lost in some lineages. The genes of the RNase A family have diversified to accomplish a variety of functions such as the digestion of RNA in food items, the innate defense against pathogen RNA, and blood vessel formation (Cho, 2006).

Pancreatic ribonuclease (RNase 1)

Eosinophil-derived neutotoxin (RNase 2)

Eosinophil cationic protein (RNase 3) and RNase 2 originated from gene primate gene duplications

RNase 4

Angiogenin (RNase 5) induces blood vessel formation.

RNase 6

RNase 7 and RNase 8 originated from primate gene duplications.

RNase 9 and RNase 10 may not function as RNases.

RNase 11

RNase 12

RNase 13


     The alcohol dehydrogenase which the liver produces belongs to the same gene family as yeast, plant, and prokaryotic alcohol dehydrogenases (Holmes, 1996).


     Crustaceans use copper-containing proteins known as hemocyanin for oxygen tranpsort in their hemolymph.  Insects lack hemocyanins but possess proteins known as hexamerins in their hemolymph.  Analysis of newly discovered molecules such as cryptocyanin indicate that oxygen binding and molting in many invertebrates are mediated by members of the hemocyanin gene family which include henocyanins, hexamerins, cryptocyanins, and prophenoloxidase (Terwilliger, 1999).


     Long chain fatty acids (LCFAs) are energy sources in both prokaryotes and eukaryotes.  The gene family of transporters for these fatty acids (FATPs) perform a conserved function in bacteria and vertebrates (including humans) (Hirsch, 1998).


Gene duplication has produced multiple ribonuclease enzymes in mammalian eosinophils (Larson, 1996).


Proteinases classified as pregnancy-associated glycoproteins (PAGs) are expressed in the placenta.  Most mammals possess only one PAG gene (including horses and zebras) while artiodactyls (relatives of the perissodactyls) may have 100 PAG genes or more.  The function of these genes is unknown and some forms are unlikely to function as enzymes.  The amplication of the PAG genes has occurred recently in the artiodactyl lineage (Hughes, 2000).



Chromosomal inversions have produced a number of variations of the third chromosome in Drosophila pseudoobscura near the amylase gene.  Different arrangements possess a characteristic number of amylase genes ranging from 1-3 (Popadic, 1995).


Haptoglobin a paralog of esterase which has lost its enzymatic function (Lundin, 1993)


The human amylase gene cluster consists of two pancreatic amylase genes, three salivary amylase genes, and two pseudogenes in a cluster on chromosome 1p21 (Gumucio, 1988).


Human gastric lipase, rat lingual lipase, and human lysosomal acid lipase are highly homologous members of a gene family (Lohse, 1997).



The arthropod digestive protease astacin, metalloendopeptidases released at the intestinal brush border in mice and humans (meptrin A and PPH respectively), BMP1, and a protein from frogs belong to the same gene family (Dumermuth, 1991).



A gene family including SIR2 genes in yeast and C. elegans and 7 sirtuins in humans function in the inactivation of heterochromatin (Onyango, 2002).


Most reactive oxygen molecules (such as hydrogen peroxide, hydroxyl radicals, and superoxide anions) are removed by reactions catalyzed by superoxide dismutases.  Mammals possess two superoxide dismutases which are unrelated despite the fact that they catalyze the same reaction: a mitochondrial enzyme which contains manganese and a cytostolic enzyme which contains zinc and copper (Fukuhara, 2002).




A family of proteins, G-protein signaling proteins (RGS) is conserved in animals and fungi which regulate the activity of G proteins.  In mammals, there are more than 20 members of this gene family, which often exist as tandem duplications (in both mice and human genomes) (Sierra, 2002).


Frataxin is a mitochondrial protein in animals which limits the accumulation of iron.  It is homologous to bacterial proteins, such as those which function in protection from tellurium (Cho, 2000).



3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) functions both in sterol synthesis in vertebrates and the synthesis of juvenile hormone and pheromones in insects (Tittiger, 2003).  Homologous enzymes are known in eubacteria, archebacteria, plants, fungi, and animals (Istvan, 2001).


      Recombination-activating genes rag1 and rag2 allow for the recombination of antibody regions in the development of the immune system.  This has become such a critical part of the immune system that mutations which inactivate these genes are lethal because of infections which subsequently develop in infants.  These genes seem to have originated from a transposon from an infections organism in the ancestor of jawed vertebrates (Ameisen, 2002)


The chromosomal region 1p21 possesses a cluster of 5 amylase genes and one amylase pseudogene which seems to be derived from an ancestral pancreatic gene.  Some of these genes appear to have arisen from a duplication followed by an inversion (Groot, 1990).


The FMR1 protein (whose mutations are responsible for fragile-X mental retardation) is an RNA-binding protein that is required for the proper development of the nervous system.  Cnidarians express a homolog at sites where nerve cells develop (Guduric-Fuchs, 2004).


Spermadhesins are secreted proteins of the male reproductive tract.  They are produced in semen of ungulates.  Humans, chimps, and dogs possess inactive spermadhesin pseudogenes (Haase, 2005).


Both invertebrates and vertebrates possess small cytoplasmic proteins which bind to nonpolar molecules.  This family of intracellular lipid-binding proteins (iLBPs) include fatty-acid binding proteins (FABPs) and cellular retinoic-acid binding proteins (CRABPs).  Their function includes the import of these substances, their transport, and their metabolism (Folli, 2005).


About 20 genes of the human genome are members of the connexin gene family. These small proteins form complexes of 6 unit oligomers and a connexon complex on one cell then interacts with a complex on a second cell. Duplications of connexin genes have produced additional genes in teleost fish (Eastman, 2006).

The protein gephyrin functions in the association of glycine receptors in neurons of the mammalian nervous system. Homologs of this protein are known throughout the major groups of living things where they function as cofactors for enzymes which utilize molybdenum. Gephyrin can replace the function of mutant molybdenum cofactors (Moco) in organisms as diverse as mammals, plants, and bacteria (Stallmeyer, 1999).

Glutamine synthetase is an enzyme which is essential to all organisms because of its roles in the synthesis of glutamine and in metabolism of nitrogen. An ancestral gene dating to the earliest cells seems to have duplicated to produce a family of GS genes found only in prokaryotes and a second family found in both prokaryotes and eukaryotes (Kumada, 1993).

Mitochondrial membranes can express uncoupling proteins which allow protons to leak through the membrane. UCP2 is expressed throughout the body and other gene family members are more specific being expressed in brain cells or brown adipose. The duplication and diversification of ancestral UCP genes had begun before the last common ancestor of the coleomates (Sokolova, 2005).


The serpin superfamily has undergone a great diversification in vertebrates to produce proteins as varied as ovalbumin in chicken egg whites to proteins which regulate inflammation and embryological development. Although most function as serine protease inhibitors, some have evolved modified functions such as signaling (e.g. angiotensinogen) and energy storage (ovalbumin). Serpins are ancient molecules and are known from all three domains of life (Benarafa, 2005).



In coelomate animals, alpha-2-macroglobulin functions as a protease inhibitor to combat proteases from infectious agents. Other members of its gene family include complement proteins and pregnancy zone proteins ( Hammond, 2005).



Lancelets express the Trk receptor AmphiTrk during the development of the nervous system. This receptor is capable of interacting with vertebrate signals such as NGF, BDGF, and several neurotropins (Benito-Guitierrez, 2005).


A variety of unrelated enzymes function as ribonucleases including the ribonuclease A superfamily and ribonucleases H, L, P and T and a variety of ribozymes (Choo, 2006).