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The entire evolutionary history of the animal gene family, Teneurin, can be summed up in three key steps, plus three salient footnotes. In a shared ancestor of all bilaterians, the first step began with gene fusions that created a protein with an amino-terminal intracellular domain bridged via a single transmembrane helix to extracellular EGF-like domains. This first step was completed with a further gene fusion: an additional carboxy-terminal stretch of about 2000 amino acids (aa) was adopted, as-a-whole, from bacteria. The 2000 aa structure in Teneurin was recently solved in three dimensions. The 2000 aa region appears in a number of bacteria, yet was co-opted solely into Teneurin, and into no other eukaryotic proteins. Outside of bilaterian animals, no Teneurins exist, with a \" caveat\" brought below, as 'the third footnote.\" Subsequent to the \"urTeneurin's\" genesis-by-fusions, all bilaterians bore a single Teneurin gene, always encoding an extraordinarily conserved Type II transmembrane protein with invariant domain content and order. The second key step was a duplication that led to an exception to singleton Teneurin genomes. A pair of Teneurin paralogs, Ten-a and Ten-m, are found in representatives of all four Arthropod sub-phyla, in: insects, crustaceans, myriapods, and chelicerates. In contrast, in every other protostome species' genome, including those of all non-Arthropod ecdysozoan phyla, only a single Teneurin gene occurs. The closest, sister, phylum of arthropods, the Onychophorans (velvet worms), bear a singleton Teneurin. Ten-a and Ten-m therefore arose from a duplication in an urArthropod only after Arthropods split from Onychophorans, but before the splits that led to the four Arthropod sub-phyla. The third key step was a quadruplication of Teneurins at the root of vertebrate radiation. Four Teneurin paralogs (Teneurins 1 through 4) arose first by a duplication of a single chordate gene likely leading to one 1/4-type gene, and one 2/3-type gene: the two copies found in extant jawless vertebrates. Relatively soon thereafter, a second duplication round yielded the -1, -2, -3, and -4 paralog types now found in all jawed vertebrates, from sharks to humans. It is possible to assert that these duplication events correlate well to the Ohno hypothesized 2R (two round) vertebrate whole genome duplication (WGD), as refined in more recent treatments. The quadruplication can therefore be placed at approximately 400 Myr ago. Echinoderms, hemichordates, cephalochordates, and urochordates have only a single copy of Teneurin in their genomes. These deuterostomes and non-vertebrate chordates provide the anchor showing that the quadruplication happened at the root of vertebrates. A first footnote must be brought concerning some of the 'invertebrate' relatives of vertebrates, among Deuterostomes. A family of genes that encode 7000 aa proteins was derived from, but is distinct from, the Teneurin family. This distinct family arose early in deuterostomes, yet persists today only in hemichordate and cephalochordate genomes. They are named here TRIPs (Teneurin-related immense proteins). As a second of three 'footnotes': a limited number of species exist with additional Teneurin gene copies. However, these further duplications of Teneurins occur for paralog types (a, m, or 1-4) only in specific lineages within Arthropods or Vertebrates. All examples are paralog duplications that evidently arose in association with lineage specific WGDs. The increased Teneurin paralog numbers correlate with WGDs known and published in bony fish, Xenopus, plus select Chelicerates lineages and Crustaceans. The third footnote, alluded to above, is that a Teneurin occurs in one unicellular species: . Teneurins are solely a metazoan, bilaterian-specific family, to the exclusion of the Kingdoms of prokaryotes, plants, fungi, and protists. The single exception occurs among the unicellular, opisthokont, closest relatives of metazoans, the choanoflagellates. There is a Teneurin in , one species of the two fully sequenced choanoflagellate species. In contrast, outside of triploblast-bilaterians, there are no Teneurins in any diploblast genomes, including even sponges - those metazoans closest to choanoflagellates. Perhaps the 'birth' of the original Teneurin occurred in a shared ancestor of and metazoans, then was lost in ' sister species, and was serially and repeatedly lost in all diploblast metazoans. Alternatively, and as favored above, it first arose in the 'urBilaterian,' then was subsequently acquired from some bilaterian via horizontal transfer by a single choanoflagellate clade. The functional partnership of Teneurins and Latrophilins was discovered in rodents through the LPH1-TENM2 interaction. Recent work extends this to further members of each family. Surveying when the interacting domains of Teneurins and Latrophilins co-exist within different organisms can give an indication of how widespread their functional cooperation might be, across bilaterians. Paralog number for the two families is relatively correlated among bilaterians, and paralog numbers underwent co-increase in the WGDs mentioned above. With co-increasing paralog numbers, the possible combinatorial pairs grow factorially. This should have a significant impact for increasing nervous system complexity. The 3 key events in the 'natural history' of the Teneurins and their Latrophilin partners coincide with the ascendance of particularly successful metazoan clades: bilaterians; arthropods; and vertebrates. Perhaps we can attribute some of this success to the unique Teneurin family, and to its partnership with Latrophilins.

Teneurins were first discovered and published in 1993 and 1994, in as and They were initially described as cell surface proteins, and as pair-rule genes. Later, they proved to be type II transmembrane proteins, and not to be pair-rule genes. might nonetheless have had an ancestral function in clock-based segmentation as a Ten-m oscillator. The turn of the millennium saw a watershed of vertebrate Teneurin discovery, which was soon complemented by Teneurin protein annotations from whole genome sequence publications. Teneurins encode proteins with essentially invariant domain order and size. The first years of Teneurin studies in many experimental systems led to key insights, and a unified picture, of Teneurin proteins.

Robust biological signaling networks evolved, through gene duplications, from simple, relatively fragile cascades. Architectural features such as layered configuration, branching and modularity, as well as functional characteristics (e.g., feedback control circuits), enable fail‐safe performance in the face of internal and external perturbations. These universal features are exemplified here using the receptor tyrosine kinase (RTK) family. The RTK module is richly mutated and overexpressed in human malignancies, and pharmaceutical interception of its signaling effectively retards growth of specific tumors. Therapy‐induced interception of RTK‐signaling pathways and the common evolvement of drug resistance are respectively considered here as manifestations of fragility and plasticity of robust networks. The systems perspective we present views pathologies as hijackers of biological robustness and offers ways for identifying fragile hubs, as well as strategies to overcome drug resistance.

Kekkon proteins negatively regulate the epidermal growth factor receptor (EGFR) during oogenesis in Drosophila . Their structural relative in mammals, LRIG1, is a transmembrane protein whose inactivation in rodents promotes skin hyperplasia, suggesting involvement in EGFR regulation. We report upregulation of LRIG1 transcript and protein upon EGF stimulation, and physical association of the encoded protein with the four EGFR orthologs of mammals. Upregulation of LRIG1 is followed by enhanced ubiquitylation and degradation of EGFR. The underlying mechanism involves recruitment of c‐Cbl, an E3 ubiquitin ligase that simultaneously ubiquitylates EGFR and LRIG1 and sorts them for degradation. We conclude that LRIG1 evolved in mammals as a feedback negative attenuator of signaling by receptor tyrosine kinases.

The Drosophila Ten-m (also called Tenascin-major, or odd Oz (odz)) gene has been associated with a pair-rule phenotype. We identified and characterized new alleles of Drosophila Ten-m to establish that this gene is not responsible for segmentation defects but rather causes defects in motor neuron axon routing. In Ten-m mutants the inter-segmental nerve (ISN) often crosses segment boundaries and fasciculates with the ISN in the adjacent segment. Ten-m is expressed in the central nervous system and epidermal stripes during the stages when the growth cones of the neurons that form the ISN navigate to their targets. Over-expression of Ten-m in epidermal cells also leads to ISN misrouting. We also found that Filamin, an actin binding protein, physically interacts with the Ten-m protein. Mutations in cheerio, which encodes Filamin, cause defects in motor neuron axon routing like those of Ten-m. During embryonic development, the expression of Filamin and Ten-m partially overlap in ectodermal cells. These results suggest that Ten-m and Filamin in epidermal cells might together influence growth cone progression.

Comparison of the genomes and proteomes of the two diptera Anopheles gambiae and Drosophila melanogaster, which diverged about 250 million years ago, reveals considerable similarities. However, numerous differences are also observed; some of these must reflect the selection and subsequent adaptation associated with different ecologies and life strategies. Almost half of the genes in both genomes are interpreted as orthologs and show an average sequence identity of about 56%, which is slightly lower than that observed between the orthologs of the pufferfish and human (diverged about 450 million years ago). This indicates that these two insects diverged considerably faster than vertebrates. Aligned sequences reveal that orthologous genes have retained only half of their intron/exon structure, indicating that intron gains or losses have occurred at a rate of about one per gene per 125 million years. Chromosomal arms exhibit significant remnants of homology between the two species, although only 34% of the genes colocalize in small \"microsyntenic\" clusters, and major interarm transfers as well as intra-arm shuffling of gene order are detected.

Anopheles gambiae is the principal vector of malaria, a disease that afflicts more than 500 million people and causes more than 1 million deaths each year. Tenfold shotgun sequence coverage was obtained from the PEST strain of A. gambiae and assembled into scaffolds that span 278 million base pairs. A total of 91% of the genome was organized in 303 scaffolds; the largest scaffold was 23.1 million base pairs. There was substantial genetic variation within this strain, and the apparent existence of two haplotypes of approximately equal frequency (\"dual haplotypes\") in a substantial fraction of the genome likely reflects the outbred nature of the PEST strain. The sequence produced a conservative inference of more than 400,000 single-nucleotide polymorphisms that showed a markedly bimodal density distribution. Analysis of the genome sequence revealed strong evidence for about 14,000 protein-encoding transcripts. Prominent expansions in specific families of proteins likely involved in cell adhesion and immunity were noted. An expressed sequence tag analysis of genes regulated by blood feeding provided insights into the physiological adaptations of a hematophagous insect.

A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies—a whole-genome assembly and a regional chromosome assembly—were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional ∼12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.