Blue boxes indicate matching between the mouse and human version of the
protein; red underlines represent shared amino acids between all three
Figure 2 represents the alignments of
IGF-1 ortholog protein sequences among humans, fruit flies, and mice
(the only three species out of the seven most studied in genomics). The
blue boxes indicate stretches of perfect alignment between the human
and mouse protein. These two proteins are remarkably similar in
sequence. Of the 70 amino acids comprising the human protein, residues
1-18, 20-26, 28-34, and 36-66 have perfect matches with the mouse
protein. This is a great deal of similarity.The Drosophila
however, does not align so easily with either the mouse or human
version of IGF-1. The amino acid subsequences that all three organisms
share have been evolutionarily conserved, and are most likely critical
to its functioning. The portions underlined in red indicate the two
longest stretches of shared amino acids between all three proteins.
Amino acids 31-33 and 45-48 (of human IGF-1) are
the 2 longest stretches of amino acid similarity shared among these
species. It seems likely that these are necessary for the protein's
function (binding to an IGF-1 receptor protein), and that mutations in
any of these amino acids could lead to
debilitating effects. It should be noted that many biological reference sites do not include the Drosophila
protein as an ortholog - the differences are simply too many ("IGF1 Orthologs"). Despite this, the Drosophila
sequence can still be useful, as we have seen above.
More orthologs of Human IGF-1 need to be examined before one can truly
declare that certain amino acids have been universally conserved. Zou et al.
reported the presence of an IGF-1 ortholog in zebrafish (2009). Other
species with known orthologs of IGF-1 include dogs, chimpanzees, cows,
rats, chickens, the African-clawed frog, and the rainbow trout
("Insulin-like growth factor 1 (somatomedin C)").
Five species with the
most closely related IGF-1 orthologs. No prokaryotes have known
orthologs of IGF-1. Permission pending from GeneCards.
Let's take a look at some of these other
orthologs (all of which, it should be noted, occur in eukaryotes).
Analysis of more protein sequences will give us a better understanding
of what has been evolutionarily conserved. An interesting comparison
will come from analyzing a less similar protein, such as Zebrafish
The following chart is an alignment of IGF-1 proteins from humans, mice, and zebrafish.
alignment of IGF-1 proteins from humans, mice, and zebrafish. The blue
boxes indicate the two longest stretches of amino acid matching among
all three species.
Among the three species we are examining
here, there are some long stretches of amino acid matching. The first
12 amino acids of human IGF-1 are conserved in zebra fish and mouse
protein, indicating that these are most likely essential for IGF-1's
proper functioning. Amino acids 54-63 from the human protein are also
conserved in mice and zebrafish. These conserved amino acids most
likely play a crucial role in binding the IGF-1 receptor.
An even more expansive look at IGF-1 orthologs can be seen below:
Figure 5. Alignments of 5 orthologs.
The first 27 amino acids of human IGF-1 are nearly all conserved - 25
of the 27 are conserved in each ortholog examined above. Clearly, the
beginning portion of this protein is most important to its function.
Why is this important?
the protein sequences of various orthologs allows us to understand
which amino acids are most critical. With this knowledge in hand, we
can examine genetic diseases associated with mutations in the IGF-1
gene that result in differing protein sequences. IGF-1 plays a critical
role in stimulating cell growth - it is classified as a growth
stimulating hormone (a somatomedin). Mutations in IGF-1 that disrupt
binding to the IGF-1 receptor (or IGF-1R) have the potential to limit
growth. Researchers have created mutant strains of mice homozygous for
mutations in IGF-1 that either die before birth or are severely stunted
(Liu et al.
Other research with IGF-1 deficiencies/mutations has resulted in some
very interesting findings. Growth hormone knockout mice (incapable of
producing IGF-1) lived extremely
long lives (Bartke et al.
2002). Bartke et al.
"that the role of IGF in the regulation of growth and adult body size
is important in mediating the effects of longetivity genes on aging and
life span" (2002). Based on this data, mutations in IGF-1 could
plausibly influence life span.
Bartke A., F. Dominici, D. Turyn, B.
Kinney, R. Steger, Kopchick JJ. 2003. Insulin-like growth factor
1 (IGF-1) and aging: controversies and new insights. Biogerontology
You can find the abstract here.
Fulton DL., YY. Li, MR. Laird, BGS Horsman, FM. Roche, Brinkman FSL.
2006. Improving the specificity of high-throughput ortholog prediction.
7: 270. Find it here
Liu JP., J. Baker, AS. Perkins, EJ. Robertson, Efstratiadis A. 1993.
Mice carrying null mutations of the genes encoding insulin-like growth
factor 1 (IGF-1) and type-1 IGF receptor (IGF1R). Cell
75: 59-72. Find it here
Zou S., H. Kamei, Z. Modi, Duan C. 2009. Zebrafish IGF Genes: Gene
Dupication, Conservation and Divergence, and Novel Roles in Midline and
Notochord Development. PLoS ONE
4(9): e7026. Find it here
IGF1 Orthologs. Nature: Cell Migration Consortium. 10 March 2010. Find it here
Insulin-like growth factor 1 (somatomedin C). GeneCards. 10 March 2010. Find it here
*Protein sequences obtained from Blast. Sequences were found after searching with human IGF-1*
*All alignments were done using ClustalW*