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"Weiss, Kenneth M"
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Mineralized Tissue and Vertebrate Evolution: The Secretory Calcium-Binding Phosphoprotein Gene Cluster
Gene duplication creates evolutionary novelties by using older tools in new ways. We have identified evidence that the genes for enamel matrix proteins (EMPs), milk caseins, and salivary proteins comprise a family descended from a common ancestor by tandem gene duplication. These genes remain linked, except for one EMP gene, amelogenin. These genes show common structural features and are expressed in ontogenetically similar tissues. Many of these genes encode secretory Ca-binding phosphoproteins, which regulate the Ca-phosphate concentration of the extracellular environment. By exploiting this fundamental property, these genes have subsequently diversified to serve specialized adaptive functions. Casein makes milk supersaturated with Ca-phosphate, which was critical to the successive mammalian divergence. The innovation of enamel led to mineralized feeding apparatus, which enabled active predation of early vertebrates. The EMP genes comprise a subfamily not identified previously. A set of genes for dentine and bone extracellular matrix proteins constitutes an additional cluster distal to the EMP gene cluster, with similar structural features to EMP genes. The duplication and diversification of the primordial genes for enamel/dentine/bone extracellular matrix may have been important in core vertebrate feeding adaptations, the mineralized skeleton, the evolution of saliva, and, eventually, lactation. The order of duplication events may help delineate early events in mineralized skeletal formation, which is a major characteristic of vertebrates.
Journal Article
Genetic Basis for the Evolution of Vertebrate Mineralized Tissue
Mineralized tissue is vital to many characteristic adaptive phenotypes in vertebrates. Three primary tissues, enamel (enameloid), dentin, and bone, are found in the body armor of ancient agnathans and mammalian teeth, suggesting that these two organs are homologous. Mammalian enamel forms on enamel-specific proteins such as amelogenin, whereas dentin and bone form on collagen and many acidic proteins, such as SPP1, coordinately regulate their mineralization. We previously reported that genes for three major enamel matrix proteins, five proteins necessary for dentin and bone formation, and milk caseins and salivary proteins arose from a single ancestor by tandem gene duplications and form the secretory calcium-binding phosphoprotein (SCPP) family. Gene structure and protein characteristics show that SCPP genes arose from the 5′ region of ancestral SPARCL1 (SPARC-like 1). Phylogenetic analysis on SPARC and SPARCL1 suggests that the SCPP genes arose after the divergence of cartilaginous fish and bony fish, implying that early vertebrate mineralization did not use SCPPs and that SPARC may be critical for initial mineralization. Consistent with this inference, we identified SPP1 in a teleost genome but failed to find any genes orthologous to mammalian enamel proteins. Based on these observations, we suggest a scenario for the evolution of vertebrate tissue mineralization, in which body armor initially formed on dermal collagen, which acted as a reinforcement of dermis. We also suggest that mammalian enamel is distinct from fish enameloid. Their similar nature as a hard structural overlay on exoskeleton and teeth is because of convergent evolution.
Journal Article
Low Frequency Variants, Collapsed Based on Biological Knowledge, Uncover Complexity of Population Stratification in 1000 Genomes Project Data
Analyses investigating low frequency variants have the potential for explaining additional genetic heritability of many complex human traits. However, the natural frequencies of rare variation between human populations strongly confound genetic analyses. We have applied a novel collapsing method to identify biological features with low frequency variant burden differences in thirteen populations sequenced by the 1000 Genomes Project. Our flexible collapsing tool utilizes expert biological knowledge from multiple publicly available database sources to direct feature selection. Variants were collapsed according to genetically driven features, such as evolutionary conserved regions, regulatory regions genes, and pathways. We have conducted an extensive comparison of low frequency variant burden differences (MAF<0.03) between populations from 1000 Genomes Project Phase I data. We found that on average 26.87% of gene bins, 35.47% of intergenic bins, 42.85% of pathway bins, 14.86% of ORegAnno regulatory bins, and 5.97% of evolutionary conserved regions show statistically significant differences in low frequency variant burden across populations from the 1000 Genomes Project. The proportion of bins with significant differences in low frequency burden depends on the ancestral similarity of the two populations compared and types of features tested. Even closely related populations had notable differences in low frequency burden, but fewer differences than populations from different continents. Furthermore, conserved or functionally relevant regions had fewer significant differences in low frequency burden than regions under less evolutionary constraint. This degree of low frequency variant differentiation across diverse populations and feature elements highlights the critical importance of considering population stratification in the new era of DNA sequencing and low frequency variant genomic analyses.
Journal Article
The Four Horsemen of the ‘Omicsalypse’: ontology, replicability, probability and epistemology
Much of modern genomics and the other ‘omics’ that tag along, assert that the causal bases of biomedical outcomes are genomically enumerable lists whose effects are predictable with ‘precision’, extensible from samples to all, and enabled by ever-greater hypothesis-free data accumulation. The assertion rests on fundamental, if often implicit assumptions, that (1) the phenomena are based on underlying law-like biological causation, and, therefore, are (2) replicable and (3) even if not deterministic, have specifiable, stable, essentially parametric, probabilities, all of which (4) essentially equates induction with deduction, enabling asymptotically accurate prediction based on past observation. These glowing promises are the four horsemen of a genocentric ‘Omicsalypse’. But what if the assumptions are wrong or appropriate only to an extent that is unknowable, even in principle? Might there be better ways to understand complex traits?
Journal Article
Phenogenetic Drift in Evolution: The Changing Genetic Basis of Vertebrate Teeth
Vertebrate mineralized tissues are vital to the adaptive evolution of various traits. Among these traits is the tooth, which consists of two characteristic mineralized tissues, a highly mineralized surface layer (enamel in tetrapods and enameloid in fish) and a softer body (dentin), both supported by basal bone. However, enamel and enameloid are significantly different in development, and dentin shows many histological variations; hence their evolution has been intensively studied. Nevertheless, their genetic basis has been revealed only in tetrapods. We previously reported that many genes involved in tetrapod tissue mineralization arose from a common ancestor and constitute the secretory calcium-binding phosphoprotein (SCPP) gene family. Now we show that teleost fish also use many SCPPs for enameloid and dentin mineralization, but none of these directly corresponds to tetrapod SCPPs. This finding suggests that teleost and tetrapod SCPP genes have experienced independent parallel duplication histories. Thus, through phenogenetic drift, the tooth has remained a stable trait in jawed vertebrates, while evolving distinct genetic bases in teleosts and tetrapods. The characteristics of teleost SCPP genes and their expression domains in tooth development suggest the possibility that enameloid arose from dentin and enamel from enameloid more than once in vertebrate evolution. In fugu (puffer fish), expression of SCPP genes is also detected in an unusual beak-like structure that shelters numerous teeth. Their expression pattern suggests that the jaw consists of the dentin beak and supportive bone. These findings illustrate the complexity of the homology concept in understanding evolution, particularly the evolution of mineralized tissues.
Journal Article
Tilting at Quixotic Trait Loci (QTL): An Evolutionary Perspective on Genetic Causation
Recent years have seen great advances in generating and analyzing data to identify the genetic architecture of biological traits. Human disease has understandably received intense research focus, and the genes responsible for most Mendelian diseases have successfully been identified. However, the same advances have shown a consistent if less satisfying pattern, in which complex traits are affected by variation in large numbers of genes, most of which have individually minor or statistically elusive effects, leaving the bulk of genetic etiology unaccounted for. This pattern applies to diverse and unrelated traits, not just disease, in basically all species, and is consistent with evolutionary expectations, raising challenging questions about the best way to approach and understand biological complexity.
Journal Article
Gene Duplication and the Evolution of Vertebrate Skeletal Mineralization
The mineralized skeleton is a critical innovation that evolved early in vertebrate history. The tissues found in dermal skeletons of ancient vertebrates are similar to the dental tissues of modern vertebrates; both consist of a highly mineralized surface hard tissue, enamel or enameloid, more resilient body dentin, and basal bone. Many proteins regulating mineralization of these tissues are evolutionarily related and form the secretory calcium-binding phosphoprotein (SCPP) family. We hypothesize here the duplication histories of SCPP genes and their common ancestors, SPARC and SPARCL1. At around the same time that Paleozoic jawless vertebrates first evolved mineralized skeleton, SPARCL1 arose from SPARC by whole genome duplication. Then both before and after the split of ray-finned fish and lobe-finned fish, tandem gene duplication created two types of SCPP genes, each residing on the opposite side of SPARCL1. One type was subsequently used in surface tissue and the other in body tissue. In tetrapods, these two types of SCPP genes were separated by intrachromosomal rearrangement. While new SCPP genes arose by duplication, some old genes were eliminated from the genome. As a consequence, phenogenetic drift occurred: while mineralized skeleton is maintained by natural selection, the underlying genetic basis has changed.
Journal Article
Genetic Pointillism versus Physiological Form
Genomics has revealed that biological causation is subtler than a pointillist dream of essentially enumerable, additive precision predictability from constitutive DNA sequences. Instead, data have revealed a higher-dimension interactive genomic landscape, that is more fundamentally fluid than precision predictability requires. This raises epistemological and ontological issues that, if properly accepted, may help leverage new ideas.
Journal Article
Having a Jolly Good Time—Together
What’s in a word? “Hybridization” is easy to say (for professors) but carries surprisingly deep meaning from an evolutionary viewpoint. Cliff Jolly’s research contributions have included important work and thought on the nature of baboon diversity and interactions. Hybridization among baboon subspecies reflects compatible genes for many different physical and behavioral traits, essentiallyalltraits, each of them complex. Modern developmental genetics has shown that a few general principles characterize the phenogenetic logic by which genes assemble embryos and maintain the complex traits and abilities of organisms, including behavior. How cooperative viability is maintained while complex adaptive traits evolve and populations diverge is a question we can begin to answer more definitively than has been possible before. A careful look leads us to challenge the nature of the Darwinian explanations that have been the standard for more than a century.
Journal Article