Publications

2007
Yano K, Gale D, Massberg S, Cheruvu PK, Monahan-Earley R, Morgan ES, Haig D, von Andrian UH, Dvorak AM, Aird WC. Phenotypic heterogeneity is an evolutionarily conserved feature of the endothelium. Blood. 2007;109 :613-5.Abstract

Mammalian endothelial cells (ECs) display marked phenotypic heterogeneity. Little is known about the evolutionary mechanisms underlying EC heterogeneity. The last common ancestor of hagfish and gnathostomes was also the last common ancestor of all extant vertebrates, which lived some time more than 500 million years ago. Features of ECs that are shared between hagfish and gnathostomes can be inferred to have already been present in this ancestral vertebrate. The goal of this study was to determine whether the hagfish endothelium displays phenotypic heterogeneity. Electron microscopy of the aorta, dermis, heart, and liver revealed ultrastructural heterogeneity of the endothelium. Immunofluorescent studies demonstrated marked differences in lectin binding between vascular beds. Intravital microscopy of the dermis revealed histamine-induced adhesion of leukocytes in capillaries and postcapillary venules, but no such adhesion in arterioles. Together, these data suggest that structural, molecular, and functional heterogeneity of the endothelium evolved as an early feature of this cell lineage.

613.full_.pdf
Haig D. Weismann rules! OK? Epigenetics and the Lamarckian temptation. Biol Philos. 2007;22 :415-428. 07weismann.pdf
2006
Haig D. Congenital bilateral absence of the vas deferens and recombination at CFTR. Eur J Hum Genet. 2006;14 :801; author reply 801. 5201622a.pdf
Haig D, Westoby M. An earlier formulation of the genetic conflict hypothesis of genomic imprinting. Nat Genet. 2006;38 :271. ng0306-271.pdf
Haig D. Intragenomic politics. Cytogenet Genome Res. 2006;113 :68-74.Abstract

The mammalian genome contains multiple genetic factions with distinct interests in the outcomes of interactions among kin. In the context of an offspring's relations with its mother, these factions are proposed to align into two 'parties', one favoring increased demand by offspring and the other favoring reduced demand. A possible alignment has inhibitors of demand located on the X chromosome and enhancers of demand located on autosomes, because X-linked loci are maternally derived two-thirds of the time by contrast to autosomal loci which are maternally derived half of the time.

Haig D. Self-imposed silence: parental antagonism and the evolution of X-chromosome inactivation. Evolution. 2006;60 :440-7.Abstract

A model is proposed for the evolution of X-chromosome inactivation (XCI) in which natural selection initially favors the silencing of paternally derived alleles of X-linked demand inhibitors. The compensatory upregulation of maternally derived alleles establishes a requirement for monoallelic expression in females. For this reason, XCI is self-reinforcing once established. However, inactivation of a particular X chromosome is not. Random XCI (rXCI) is favored over paternal XCI because rXCI reduces the costs of functional hemizygosity in females. Once present, rXCI favors the evolution of locus-by-locus imprinting of X-linked loci, which creates an evolutionary dynamic in which different chromosomes compete to remain active.

haig-2006-evolution.pdf
Haig D, Wilczek A. Sexual conflict and the alternation of haploid and diploid generations. Philos Trans R Soc Lond B Biol Sci. 2006;361 :335-43.Abstract

Land plants possess a multicellular diploid stage (sporophyte) that begins development while attached to a multicellular haploid progenitor (gametophyte). Although the closest algal relatives of land plants lack a multicellular sporophyte, they do produce a zygote that grows while attached to the maternal gametophyte. The diploid offspring shares one haploid set of genes with the haploid mother that supplies it with resources and a paternal haploid complement that is not shared with the mother. Sexual conflict can arise within the diploid offspring because the offspring's maternal genome will be transmitted in its entirety to all other sexual and asexual offspring that the mother may produce, but the offspring's paternally derived genes may be absent from these other offspring. Thus, the selective forces favouring the evolution of genomic imprinting may have been present from the origin of modern land plants. In bryophytes, where gametophytes are long-lived and capable of multiple bouts of asexual and sexual reproduction, we predict strong sexual conflict over allocation to sporophytes. Female gametophytes of pteridophytes produce a single sporophyte and often lack means of asexual reproduction. Therefore, sexual conflict is predicted to be attenuated. Finally, we explore similarities among models of mate choice, offspring choice and segregation distortion.

rstb20051794.pdf
2005
Yuan HT, Haig D, Ananth Karumanchi S. Angiogenic factors in the pathogenesis of preeclampsia. Curr Top Dev Biol. 2005;71 :297-312.Abstract

Preeclampsia affects 5-10% of pregnancies and is responsible for substantial maternal and neonatal morbidity and mortality. It is believed to be a two-stage disease with an initial placental trigger with no maternal symptoms followed by a maternal syndrome characterized by hypertension, proteinuria, and endothelial dysfunction. The first stage is thought to be due to shallow cytotrophoblast invasion of maternal spiral arterioles leading to placental insufficiency. The diseased placenta in turn releases soluble angiogenic factors that induce systemic endothelial dysfunction and clinical preeclampsia during the second stage. This review will discuss the role of circulating angiogenic factors of placental origin as potential mediators of the systemic endothelial dysfunction and the clinical syndrome of preeclampsia and provide an evolutionary explanation for this phenomenon.

1-s2.0-s0070215305710097-main.pdf
Haig D. The complex history of distal human chromosome 1q. Genomics. 2005;86 :767-70.Abstract

Human chromosome 1 has been claimed to be a conserved ancestral chromosome of eutherian mammals. However, two small regions from distal 1q (with orthology to mouse chromosome 11) appear to have a different history. These two regions are proposed to have been added to the ancestor of human chromosome 1 as a single block that was subsequently disrupted by a paracentric inversion. The translocation and inversion appear to have occurred at some time after the primate lineage diverged from a common ancestor with rodents. Reconstruction of the history of distal human chromosome 1q is complicated by the "reuse" of breakpoints in different mammalian lineages and by coincidental shared synteny between humans and cats.

1-s2.0-s0888754305002806-main.pdf
Brandvain Y, Haig D. Divergent mating systems and parental conflict as a barrier to hybridization in flowering plants. Am Nat. 2005;166 :330-8.Abstract

Parental conflicts can lead to antagonistic coevolution of the sexes and of parental genomes. Within a population, the resulting antagonistic effects should balance, but crosses between populations can reveal conflict. Parental conflict is less intense in self-pollinating plants than in outcrossers because outcrossing plants are pollinated by multiple pollen donors unrelated to the seed parent, while a self-pollinating plant is primarily pollinated by one individual (itself). Therefore, in crosses between plants with differing mating systems, outcrossing parents are expected to "overpower" selfing parents. We call this the weak inbreeder/strong outbreeder (WISO) hypothesis. Prezygotically, such overpowering can alter pollination success, and we argue that our hypothesis explains a common pattern of unilateral incompatibility, in which pollen from self-incompatible populations fertilizes ovules of self-compatible individuals but the reciprocal cross fails. A postzygotic manifestation of overpowering is aberrant seed development due to parent-of-origin effects such as genomic imprinting. We evaluate evidence for the WISO hypothesis by reviewing published accounts of crosses between plants of different mating systems. Many, but not all, of such reports support our hypothesis. Since parental conflicts can perturb fertilization and development, such conflicts may strengthen reproductive barriers between populations, contributing to speciation.

haig_divergentmatingsystems.pdf
Ubeda F, Haig D. On the evolutionary stability of Mendelian segregation. Genetics. 2005;170 :1345-57.Abstract

We present a model of a primary locus subject to viability selection and an unlinked locus that causes sex-specific modification of the segregation ratio at the primary locus. If there is a balanced polymorphism at the primary locus, a population undergoing Mendelian segregation can be invaded by modifier alleles that cause sex-specific biases in the segregation ratio. Even though this effect is particularly strong if reciprocal heterozygotes at the primary locus have distinct viabilities, as might occur with genomic imprinting, it also applies if reciprocal heterozygotes have equal viabilities. The expected outcome of the evolution of sex-specific segregation distorters is all-and-none segregation schemes in which one allele at the primary locus undergoes complete drive in spermatogenesis and the other allele undergoes complete drive in oogenesis. All-and-none segregation results in a population in which all individuals are maximally fit heterozygotes. Unlinked modifiers that alter the segregation ratio are unable to invade such a population. These results raise questions about the reasons for the ubiquity of Mendelian segregation.

1345.full_.pdf
Mix LJ, Haig D, Cavanaugh CM. Phylogenetic analyses of the core antenna domain: investigating the origin of photosystem I. J Mol Evol. 2005;60 :153-63.Abstract

Phototrophy, the conversion of light to biochemical energy, occurs throughout the Bacteria and plants, however, debate continues over how different phototrophic mechanisms and the bacteria that contain them are related. There are two types of phototrophic mechanisms in the Bacteria: reaction center type 1 (RC1) has core and core antenna domains that are parts of a single polypeptide, whereas reaction center type 2 (RC2) is composed of short core proteins without antenna domains. In cyanobacteria, RC2 is associated with separate core antenna proteins that are homologous to the core antenna domains of RC1. We reconstructed evolutionary relationships among phototrophic mechanisms based on a phylogeny of core antenna domains/proteins. Core antenna domains of 46 polypeptides were aligned, including the RC1 core proteins of heliobacteria, green sulfur bacteria, and photosystem I (PSI) of cyanobacteria and plastids, plus core antenna proteins of photosystem II (PSII) from cyanobacteria and plastids. Maximum likelihood, parsimony, and neighbor joining methods all supported a single phylogeny in which PSII core antenna proteins (PsbC, PsbB) arose within the cyanobacteria from duplications of the RC1-associated core antenna domains and accessory antenna proteins (IsiA, PcbA, PcbC) arose from duplications of PsbB. The data indicate an evolutionary history of RC1 in which an initially homodimeric reaction center was vertically transmitted to green sulfur bacteria, heliobacteria, and an ancestor of cyanobacteria. A heterodimeric RC1 (=PSI) then arose within the cyanobacterial lineage. In this scenario, the current diversity of core antenna domains/proteins is explained without a need to invoke horizontal transfer.

art3a10.10072fs00239-003-0181-2.pdf
Lukhtanov VA, Kandul NP, Plotkin JB, Dantchenko AV, Haig D, Pierce NE. Reinforcement of pre-zygotic isolation and karyotype evolution in Agrodiaetus butterflies. Nature. 2005;436 :385-9.Abstract

The reinforcement model of evolution argues that natural selection enhances pre-zygotic isolation between divergent populations or species by selecting against unfit hybrids or costly interspecific matings. Reinforcement is distinguished from other models that consider the formation of reproductive isolation to be a by-product of divergent evolution. Although theory has shown that reinforcement is a possible mechanism that can lead to speciation, empirical evidence has been sufficiently scarce to raise doubts about the importance of reinforcement in nature. Agrodiaetus butterflies (Lepidoptera: Lycaenidae) exhibit unusual variability in chromosome number. Whereas their genitalia and other morphological characteristics are largely uniform, different species vary considerably in male wing colour, and provide a model system to study the role of reinforcement in speciation. Using comparative phylogenetic methods, we show that the sympatric distribution of 15 relatively young sister taxa of Agrodiaetus strongly correlates with differences in male wing colour, and that this pattern is most likely the result of reinforcement. We find little evidence supporting sympatric speciation: rather, in Agrodiaetus, karyotypic changes accumulate gradually in allopatry, prompting reinforcement when karyotypically divergent races come into contact.

nature03704.pdf
2004
Haig D, Henikoff S. Deciphering the genomic palimpsest. Curr Opin Gen Dev. 2004;14 :599-602. 1-s2.0-s0959437x04001595-main.pdf
Haig D. The (dual) origin of epigenetics. Cold Spring Harb Symp Quant Biol. 2004;69 :67-70. cold_spring_harb_symp_quant_biol-2004-haig-sqb.2004.69.67.pdf
Haig D. Evolutionary conflicts in pregnancy and calcium metabolism--a review. Placenta. 2004;25 Suppl A :S10-5.Abstract

The maternal-fetal unit contains three distinct haplotypes at each locus: the maternally derived fetal haplotype (MDFH) that is shared by the mother and fetus, the paternally derived fetal haplotype (PDFH), and the non-inherited maternal haplotype (NIMH). The evolutionary forces acting on these haplotypes are distinct. The NIMH is absent from the offspring and could benefit from early abortion if this enhances the probability of the mother conceiving again and producing an offspring that inherits the NIMH. This raises the possibility that some forms of recurrent spontaneous abortion may be caused by non-inherited haplotypes. Such 'selfish' behaviour would be opposed by other components of the maternal genome. Natural selection acting on genes expressed in fetuses (or their placentae) favours greater maternal investment in the fetus than does natural selection acting on genes expressed in mothers. Furthermore, in the presence of genomic imprinting, the PDFH favours greater levels of investment in the fetus than does the MDFH. These conflicts are illustrated using the example of maternal-fetal conflicts over the supply of calcium. Inactivation of the paternal copy of GNAS in proximal renal tubule is interpreted as a measure to maintain fetal bone mineralization in times of calcium stress at the expense of the maternal skeleton.

1-s2.0-s0143400404000207-main.pdf
Haig D. Genomic imprinting and kinship: how good is the evidence?. Annu Rev Genet. 2004;38 :553-85.Abstract

The kinship theory of genomic imprinting proposes that parent-specific gene expression evolves at a locus because a gene's level of expression in one individual has fitness effects on other individuals who have different probabilities of carrying the maternal and paternal alleles of the individual in which the gene is expressed. Therefore, natural selection favors different levels of expression depending on an allele's sex-of-origin in the previous generation. This review considers the strength of evidence in support of this hypothesis for imprinted genes in four "clusters," associated with the imprinted loci Igf2, Igf2r, callipyge, and Gnas. The clusters associated with Igf2 and Igf2r both contain paternally expressed transcripts that act as enhancers of prenatal growth and maternally expressed transcripts that act as inhibitors of prenatal growth. This is consistent with predictions of the kinship theory. However, the clusters also contain imprinted genes whose phenotypes as yet remain unexplained by the theory. The principal effects of imprinted genes in the callipyge and Gnas clusters appear to involve lipid and energy metabolism. The kinship theory predicts that maternally expressed transcripts will favor higher levels of nonshivering thermogenesis (NST) in brown adipose tissue (BAT) of animals that huddle for warmth as offspring. The phenotypes of reciprocal heterozygotes for Gnas knockouts provide provisional support for this hypothesis, as does some evidence from other imprinted genes (albeit more tentatively). The diverse effects of imprinted genes on the development of white adipose tissue (WAT) have so far defied a unifying hypothesis in terms of the kinship theory.

annurev2egenet2e372e1108012e142741.pdf
Haig D. The inexorable rise of gender and the decline of sex: social change in academic titles, 1945-2001. Arch Sex Behav. 2004;33 :87-96.Abstract

More than 30 million titles of "academic" articles, from the years 1945-2001, were surveyed for occurrences of the words sex and gender. At the beginning of this period, uses of gender were much rarer than uses of sex, and often used in the sense of a grammatical category. By the end of this period, uses of gender outnumbered uses of sex in the social sciences, arts, and humanities. Within the natural sciences, there was now more than 1 use of gender for every 2 uses of sex. The beginnings of this change in usage can be traced to Money's introduction of the concept of "gender role" in 1955 (J. Money, 1955). However, the major expansion in the use of gender followed its adoption by feminists to distinguish the social and cultural aspects of differences between men and women (gender) from biological differences (sex). Since then, the use of gender has tended to expand to encompass the biological, and a sex/gender distinction is now only fitfully observed.

art3a10.10232fb3aaseb.0000014323.56281.0d.pdf
Kandul NP, Lukhtanov VA, Dantchenko AV, Coleman JW, Sekercioglu CH, Haig D, Pierce NE. Phylogeny of Agrodiaetus Hubner 1822 (Lepidoptera: Lycaenidae) inferred from mtDNA sequences of COI and COII and nuclear sequences of EF1-alpha: karyotype diversification and species radiation. Syst Biol. 2004;53 :278-98.Abstract

Butterflies in the large Palearctic genus Agrodiaetus (Lepidoptera: Lycaenidae) are extremely uniform and exhibit few distinguishing morphological characters. However, these insects are distinctive in one respect: as a group they possess among the greatest interspecific karyotype diversity in the animal kingdom, with chromosome numbers (n) ranging from 10 to 125. The monophyly of Agrodiaetus and its systematic position relative to other groups within the section Polyommatus have been controversial. Characters from the mitochondrial genes for cytochrome oxidases I and II and from the nuclear gene for elongation factor 1 alpha were used to reconstruct the phylogeny of Agrodiaetus using maximum parsimony and Bayesian phylogenetic methods. Ninety-one individuals, encompassing most of the taxonomic diversity of Agrodiaetus, and representatives of 14 related genera were included in this analysis. Our data indicate that Agrodiaetus is monophyletic. Representatives of the genus Polyommatus (sensu stricto) are the closest relatives. The sequences of the Agrodiaetus taxa in this analysis are tentatively arranged into 12 clades, only 1 of which corresponds to a species group traditionally recognized in Agrodiaetus. Heterogeneous substitution rates across a recovered topology were homogenized with a nonparametric rate-smoothing algorithm before the application of a molecular clock. Two published estimates of substitution rates dated the origin of Agrodiaetus between 2.51 and 3.85 million years ago. During this time, there was heterogeneity in the rate and direction of karyotype evolution among lineages within the genus. Karyotype instability has evolved independently three times in the section Polyommatus, within the lineages Agrodiaetus, Lysandra, and Plebicula. Rapid karyotype diversification may have played a significant role in the radiation of the genus Agrodiaetus.

syst_biol-2004-kandul-278-98.pdf
Ubeda F, Haig D. Sex-specific meiotic drive and selection at an imprinted locus. Genetics. 2004;167 :2083-95.Abstract

We present a one-locus model that breaks two symmetries of Mendelian genetics. Whereas symmetry of transmission is breached by allowing sex-specific segregation distortion, symmetry of expression is breached by allowing genomic imprinting. Simple conditions for the existence of at least one polymorphic stable equilibrium are provided. In general, population mean fitness is not maximized at polymorphic equilibria. However, mean fitness at a polymorphic equilibrium with segregation distortion may be higher than mean fitness at the corresponding equilibrium with Mendelian segregation if one (or both) of the heterozygote classes has higher fitness than both homozygote classes. In this case, mean fitness is maximized by complete, but opposite, drive in the two sexes. We undertook an extensive numerical analysis of the parameter space, finding, for the first time in this class of models, parameter sets yielding two stable polymorphic equilibria. Multiple equilibria exist both with and without genomic imprinting, although they occurred in a greater proportion of parameter sets with genomic imprinting.

2083.full_.pdf

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