INTRODUCTION

The word vector is derived from the Latin and means ‘bearer’ or ‘one who does something’, but for the purposes of this chapter, we can use the term as defined by Gordh & Headrick (2001) as an arthropod that carries disease-producing organisms to a vertebrate host. A wide variety of arthropods are involved as vectors in pathogen transmission cycles but the focus of this chapter is the mosquito. To date, there are at least 537 named arthropod-borne viruses (arboviruses) (Karabatsos, 1985), encompassing species from many genera, examples of which are given in Table 1. With one exception (African swine fever virus, transmitted by ticks) all of the viruses regarded as true arboviruses have an RNA genome. The vast majority of arboviruses (e.g. Togaviridae, Flaviviridae, Bunyaviridae) are enveloped, i.e. the nucleocapsid is surrounded by a lipid-containing envelope. A few (e.g. Reoviridae) are non-enveloped. Most of these (e.g. bluetongue virus and Colorado tick fever virus) are transmitted by midges and ticks. Fewer than 20 have been isolated from mosquitoes and only lebombo and Orungo have been associated with human infections. As discussed by Mitchell (1983), because arboviruses are typically not pathogenic to their insect hosts, it has been hypothesized that they may have evolved in insects and later became infectious to vertebrates. Tick-borne arboviruses (see review by Nuttall & Labuda, 2003) and the true insect viruses (e.g. nuclear polyhedrosis viruses) that infect and replicate in mosquitoes, but are not transmitted to vertebrate hosts (Miller & Ball, 1998), are not considered in this chapter. Given that almost all mosquito-borne viruses are enveloped and have an RNA genome, unless specified otherwise, this review therefore focuses on this predominant group of arboviruses.

INTRODUCTION

Invertebrates, particularly insects, act as vectors of the most debilitating diseases in many already socially and economically compromised populations of the developing world. The diseases vectored include malaria, sleeping sickness, Chagas’ disease, leishmaniasis, lymphatic filariases and river blindness, dengue and yellow fever, and schistosomiasis. Only the latter is transmitted by non-insectan invertebrates, i.e. snails of the genus Biomphalaria. Hurd (2003) recently pointed out that of the ten most important tropical diseases affecting the poorer nations, eight of these are transmitted by invertebrate vectors (Table 1). In addition, and often underestimated in importance since they are probably second only to mosquitoes as vectors of human infectious diseases (Parola & Raoult, 2001), are the ticks. In fact, in the USA ticks transmit more vector-borne diseases than any other vector (US Centers for Disease Control and Prevention, 1999). The diseases transmitted by ticks include Lyme borreliosis, tick-borne encephalitis, ehrlichiosis and babesiosis (Gratz, 1999).

The reason that insects are particularly widespread vectors undoubtedly reflects the success of this group, occupying almost every habitat on earth in vast numbers. In addition, their power of flight, their extraordinarily well developed sense organs and their haematophagous habit have made them ideal vehicles for transmitting human blood-borne diseases. Since many insects live in places infested with pathogens and parasites they can only do so due to the extreme efficiency of their immune defences so that any invading parasite must counteract these defences to survive.

Thus, most parasites are not simply passively transported from human to human by their vectors, but interact intimately with their invertebrate hosts, usually undergoing significant biochemical and molecular modifications to survive, differentiate and multiply in their vectors.

INTRODUCTION

It has been known for a long time that arthropods requiring blood meals induce pronounced immune responses in the host on which they feed (Trager, 1939). These, together with the wide range of haemostatic mechanisms that are employed by the host to avoid blood loss, present a formidable barrier to the arthropod' essential need for regular blood meals in order to moult or produce eggs.

The immune responses first recognized were in those vector–host interactions where the arthropod remains attached to its host for a long period – days or often weeks. This is true of many ticks. The much cited work of William Trager (1939) is recognized as one of the seminal studies on anti-tick resistance and, during the past 60 years, a great deal has been learned about the numerous underlying mechanisms.

It is not surprising that such a lengthy and intimate association leads to cellular and humoral responses to vector antigens. However, it is now equally clear that such responses can also develop to haematophagous arthropods that feed rapidly and then leave the host. Notable here are insects of medical importance such as mosquitoes, sandflies and black flies.

Extensive studies have shown that, in both the slow-feeding (tick) and rapid-feeding (insect) arthropods, there is an array of immunomodulatory factors to counter the induction of immune responses, to deflect the immunity away from mechanisms that are harmful to the arthropod, or to lessen the effect of these if they do occur.

INTRODUCTION – BIOLOGICAL CONSTRAINTS ON PATHOGENS’ USE OF TICKS AS VECTORS

All vector-borne disease systems involve a triangle of dynamic reciprocal interactions between vector, host and pathogen, which is subject to two major classes of constraints. The intrinsic physical, physiological, cellular barriers determine whether the route of transmission is possible. The pathogen must be adapted to invade, establish and survive in vertebrate and invertebrate tissues alternately, and is also at the mercy of the vector–host interaction upon which depends the passage of fluids (typically vertebrate blood and invertebrate saliva) as a vehicle for infective particles. Transmission is not simply a mechanical matter, but rather a biological process whose complexity at the cellular and molecular level is still the focus of much research aimed at developing blocking agents. These biological barriers, which constitute the innate immunity of host and vector, are not absolute, but become more or less leaky through slow evolutionary change. By comparison, the second class of constraints, ecological and epidemiological hurdles, may change much more rapidly. They depend on the quantitative balance between all the factors determining the rates of transmission: transmission may be biologically possible but may not always occur effectively enough to allow persistent cycles of transmission. Such hurdles are determined to a large extent by the impact of extrinsic multifactorial environmental factors on the vector–host–pathogen triangle, and also by the impact of intrinsic factors such as host acquired immunity.

In this essay, I suggest that the evolution of tick-borne pathogens is driven by intrinsic biological barriers, but is directed and constrained by extrinsic environmental factors.

INTRODUCTION

The first discovery of human disease transmission by a vector species was in 1877, when Patrick Manson (who later founded the Royal Society of Tropical Medicine and Hygiene in London) was able to show that transmission of the nematode worms causing lymphatic filariasis involved haematophagous mosquitoes (Manson, 1878). Since that time, hundreds of vector-borne diseases have been described, usually involving arthropod vectors which may transmit not only helminths but also protozoa, bacteria or viruses to cause major epidemics of diseases such as malaria, plague, trypanosomiasis, leishmaniasis, louse-borne typhus, dengue fever, yellow fever, Japanese encephalitis and West Nile fever. The numbers of people who are affected by vector-borne diseases in the world belies the imagination. For example, 750 million people in 76 countries live in areas of endemic filariasis, and an estimated 118 million of them are infected with filariae (World Health Organization, 1995). In India alone, 50000–100000 people die each year from visceral leishmaniasis. Malaria, the most important protozoal disease infecting humans, occurs in areas where Anopheles mosquitoes are present, and causes some 300–500 million clinical cases and approximately 1·2 million deaths worldwide each year. Malaria is the commonest vector-borne disease imported into the USA, and vector-competent Anopheles mosquitoes exist there.

Apart from yellow fever, which can now be controlled effectively by vaccination, most prevention and control programmes have been based on control of the arthropod vector, but a number of factors such as resistance to insecticides and drugs have combined to cause a resurgence of many vector-borne diseases since the 1970s (Gubler, 1998).

This chapter provides an overview of the most important human diseases that are transmitted by an arthropod vector.

INTRODUCTION

Bunyaviruses comprise the largest family of arthropod-transmitted viruses. Of the 300 or so viruses in the family Bunyaviridae more than half are transmitted by mosquitoes (Calisher, 1996). A number of these viruses cause disease in man or animals, although thus far many have not been associated with human illness. The family is classified into five genera, Orthobunyavirus, Hantavirus, Nairovirus, Phlebovirus and Tospovirus, and each genus is associated with a principal arthropod vector, except the hantaviruses, which have no arthropod involvement in their life cycle. Tospoviruses are transmitted by thrips to plants, nairoviruses primarily by ticks, and orthobunyaviruses predominantly by mosquitoes. The Phlebovirus genus contains viruses transmitted by phlebotomine flies, ticks and, notably for Rift Valley fever virus, mosquitoes as well. This chapter will deal with the interactions between orthobunyaviruses and mosquitoes.

BUNYAVIRUS CHARACTERISTICS

All bunyaviruses have a tri-segmented single-stranded RNA genome of negative-sense (or a variant of negative-sense, termed ambisense) polarity. The genomic RNA segments are called L (large), M (medium) and S (small). All family members encode four structural proteins – two glycoproteins called Gn and Gc according to their position within the primary gene product, a nucleoprotein, N, that encapsidates the genomic (and antigenomic) RNA segments and an RNA-dependent RNA polymerase, called L protein. The pattern of sizes of the viral proteins and the RNAs is conserved within a genus (Elliott et al., 2000). Viruses in some genera also encode non-structural proteins on their M and/or S RNA segments, termed NSm and NSs, respectively.

INTRODUCTION

Human granulocytic ehrlichiosis (HGE) is an emerging zoonosis caused by Anaplasma phagocytophilum, an obligate intracellular bacterium with a unique tropism for neutrophils (Dumler et al., 2001; Chen et al., 1994). Since documentation of the first human case in 1994, HGE has been increasingly recognized in the United States (US) and Europe. Cases of HGE occur in areas endemic for ticks of the Ixodes persulcatus complex, which are vectors for the disease. In the US, these areas comprise the Northeast, the upper Midwest and northern California (Dumler & Bakken, 1998; Richter et al., 1996; Telford et al., 1996; Pancholi et al., 1995; Chen et al., 1994). Cases of or serological evidence for HGE have been documented in the following European countries – Slovenia, the Netherlands, Sweden, Norway, Spain, Croatia, Poland (Blanco & Oteo, 2002), the Czech Republic (Hulinska et al., 2002), Belgium (Guillaume et al., 2002), Greece (Daniel et al., 2002), Germany (Fingerle et al., 1999), Bulgaria (Christova & Dumler, 1999), Denmark (Lebech et al., 1998) and Switzerland (Pusterla et al., 1998). The annual incidence of HGE in these areas ranges from 2.3 to 16.1 cases per 100 000 persons (McQuiston et al., 1999). In one study, however, 71 of 475 Wisconsin resident serum samples contained antibodies against the HGE agent, which suggests that the annual incidence in this area may be considerably higher (Bakken et al., 1998). In nature, A. phagocytophilum cycles between its tick vector and mammalian hosts, the primary of which are the white-footed mouse, Peromyscus leucopus, and the whitetailed deer, Odocoileus virginianus. Humans are accidental hosts (Dumler & Bakken, 1998; Ogden et al., 1998).

INTRODUCTION

Drosophila has been an excellent model for the mechanistic studies of innate immunity (Hoffmann, 2003). Recently, a new RNA-based antiviral immunity with features of both innate and adaptive immunities has been described in Drosophila and Anopheles cells (Li et al., 2002, 2004). This RNA-silencing-mediated immunity is characterized by the production of pathogen-derived, 22-nt small RNAs that serve as specificity determinants inside a multi-subunit complex. Similar to innate immunity, however, the new invertebrate antiviral response is capable of a rapid virus clearance in the absence of a virus-encoded suppressor of RNA silencing. The discovery of a new antiviral pathway in insects opens up the possibility of using this pathway to prevent transmission of vector-borne virus pathogens such as dengue and West Nile viruses.

THE RNA-SILENCING PATHWAY

Homology-dependent gene silencing was discovered in transgenic plants in a form of co-suppression between introduced transgenes or between a transgene and its homologous endogenous gene (Matzke et al., 1989; Napoli et al., 1990; Van der Krol et al., 1990). Similar gene-silencing phenomena have subsequently been described in a wide range of eukaryotic organisms such as fungi, worms, flies and mammals (Denli & Hannon, 2003; Fire et al., 1998). A generic term, RNA silencing (Ding, 2000), has been used to describe these related RNA-guided gene regulatory mechanisms variously termed post-transcriptional gene silencing (PTGS) in plants, quelling in fungi and RNA interference (RNAi) in animals.

A core feature of RNA silencing detected in all organisms is the production of 21–26-nt small RNAs from structured or double-stranded RNA (dsRNA) by the endoribonuclease Dicer (Bernstein et al., 2001; Hamilton et al., 2002; Hamilton & Baulcombe, 1999; Hammond et al., 2000; Zamore et al., 2000).

Vector-borne diseases are a major threat to public health throughout the world. They include major human diseases such as malaria, trypanosomiasis and dengue, and others that principally affect animal populations such as theileriosis and West Nile fever. The study of vector-borne diseases has gone through a period when there was little impetus for research. However, through programmes such as the ‘Great Neglected Diseases Network’ and the Tropical Diseases Research Programme of WHO in the 1980s scientific attention was redirected to vector-borne diseases. More recently initiatives such as the ‘Roll Back Malaria’ programme have moved the subject on further.

In industrialized countries vector-control programmes have eradicated the important vector-borne diseases although increasing international travel has meant that diseases acquired in the tropics are no longer rare in developed world clinical practice. Climate change, industrialization, changing land use and increasing population have all had a profound impact on vector-borne diseases, resulting in epidemics spread. The recent appearance of West Nile virus in North America and Nipah virus in Malaysia has been responsible for dramatic epidemics in animal and human populations with considerable numbers of human deaths. These epidemics have caught the attention of the public.

Vector-borne infections require an extraordinary integration of host and pathogen. Unravelling these interrelationships is a challenge for biologists. The subtle ways in which parasites control their vectors, and the filaria that contain Wolbachia spp., essential to survival and fertility, are examples of elegant and effective co-evolution.

This symposium volume brings together internationally recognized experts to explore the complexity of host–pathogen–vector interactions.

INTRODUCTION

Obligate parasites all rely on their host for survival. Transfer from one host to another is thus a key aspect of their life cycle, ensuring both their maintenance (vertical and horizontal transmission) and spread (primarily horizontal transmission) in the environment. Vertical transmission, i.e. the passage of a parasite directly from one host to its descendant(s), is a strategy that does not involve passage outside the host, and so maintains the parasite in an amiable environment. However, the success of this transmission strategy depends on the survival of the host line. Furthermore, it restricts parasite spread within the host population. In fact, the survival of the parasite population is directly related to host fitness. Thus vertical transmission may be expected to lead to parasite populations with lower virulence or to non-pathogenic interactions (Frank, 1996; Day, 2001; Weiss, 2002).

All pathogens have evolved additional (or even exclusive) strategies for horizontal transmission, with an impressive diversity of mechanisms that will be the focus of the present chapter. Pathogens are found among viruses, bacteria, fungi, protozoa and metazoa but the tremendous richness of transmission strategies mentioned above is certainly best illustrated by viruses. Examples of horizontal transmission of organisms other than viruses are described in several sections of this symposium volume. Some viruses have, like other pathogens, developed the ability to transfer from infected to healthy hosts by contact or through passage in the external medium, via a variety of propagating forms (Kuno, 2001). Most viruses, however, exploit an additional organism, itself travelling from host to host, as a transportation device (referred to as a vector).

INTRODUCTION

Wolbachia are obligate intracellular bacteria that infect a wide range of invertebrate hosts (O'Neill et al., 1997). As a genus they are most closely related to the arthropodtransmitted bacteria Ehrlichia within the Rickettsiaceae (Fig. 1a). Wolbachia are widespread throughout insects and also infect crustaceans, mites and filarial nematodes. The extent of their distribution is still not well understood but they are already among the most abundant and widespread bacterial symbionts so far described. Wolbachia have evolved a diversity of associations with their hosts, ranging from being pathogens and reproductive parasites in arthropods to mutualists in filarial nematodes. A common target of Wolbachia is the host's reproductive system, which is manipulated to enhance the spread of the symbiont throughout populations. In arthropods, the bacteria have developed a bewildering repertoire of strategies with which to manipulate host reproduction. They can affect the fertility of hosts by controlling compatibility between infected males and uninfected females (cytoplasmic incompatibility), alter sex ratios by killing males or by inducing asexual production of female offspring (parthenogenesis) and even turn males into females (feminization). Not all associations, however, are weighted in favour of the bacteria. In a species of parasitic wasp which feeds on Drosophila, egg production is dependent on Wolbachia (Dedeine et al., 2001), and in filarial nematodes the symbionts are strict mutualists, essential for larval and embryo development and the survival of adult worms (Taylor, 2002). The diversity of association and phenotype in Wolbachia provides an excellent opportunity to study the nature, mechanisms and evolution of these different host–symbiont interactions.

INTRODUCTION

In 430 BC, Hippocrates said ‘Whoever would study medicine aright must learn of the following subjects. First, he must consider the effect of the seasons of the year and the differences between them. Second, he must study the warm and cold winds, both those which are common to every country and those peculiar to a particular locality.’

From this we can see that the influence of climate and environmental variables on infectious diseases has been a topic of interest to medicine for over 2000 years. Recently there has been an increase in this interest spurred on by the various climate change scenarios that have been put forward and highlighted by the fact that 9 of the 10 warmest years on record have occurred since 1990, thereby supporting the concept of ongoing climate change. Furthermore, recent climate models project an increase in global mean temperature of between 1.4 and 5.8 °C during the 21st century (Intergovernmental Panel on Climate Change, 2001). It is further predicted that maximum warming will occur at high latitudes and during the winter, and that nighttime temperatures will increase more than daytime temperatures (Karl et al., 1993; Kukla & Karl, 1993; McMichael et al., 1996).

In the context of vector-borne diseases, these predicted temperature increases, and accompanying climatic changes in rainfall patterns and extreme weather events (for example increased windiness), are likely to have a variable but significant effect. By definition, vector-borne diseases possess a vector stage, usually an insect, tick, crustacean or mollusc, which is poikilothermic and therefore peculiarly liable to be profoundly influenced by climatic variables, especially temperature.

INTRODUCTION

The life cycle of the causative agent of human malaria, the protozoan Plasmodium, involves transmission through both humans and the mosquito vector. Malaria can therefore be tackled on three distinct biological fronts. The most explored is the development of vaccines or drugs that kill the parasite during its passage through the human host. Drugs such as chloroquine have been used with considerable success; however, the emergence of resistance to these drugs has compromised their effectiveness in many regions of the world. Considerable efforts have been directed towards the development of vaccines for malaria; however, the ability of the parasite to evade the human acquired immune response has so far frustrated these attempts. The publication of the complete genomic sequence of Plasmodium falciparum (Gardner et al., 2002), the major malaria pathogen in sub-Saharan Africa, has rejuvenated efforts to develop drugs that will specifically target the parasite while minimizing side effects on the human host.

Development of malaria control or eradication strategies based on mosquito vector control has traditionally involved the use of chemical insecticides with or without elimination or reduction of excess standing water. These have been successful in terms of reducing or eliminating malaria from specific geographical regions. Regions of Europe, Asia, the Americas and Australia have been rendered malaria-free as a consequence of these area-wide strategies. The effectiveness of this approach has, however, diminished with the cessation of the application of DDT, the rapid emergence of resistance to insecticides amongst mosquito populations, and the overall reluctance of communities to accept the spraying of any chemical insecticide.

YERSINIA PESTIS, A NEWLY EMERGED ARTHROPOD-BORNE AGENT

Bacterial pathogens transmitted by blood-feeding arthropods present serious public health problems worldwide and new ones continue to be recognized, for example the agents of Lyme disease, ehrlichiosis and cat scratch disease. Arthropod-borne transmission is relatively rare among the prokaryotes, but has evolved independently in a phylogenetically diverse group of eubacteria, including the rickettsiae, spirochaetes in the genus Borrelia, and the Gram-negative or proteobacteria Yersinia pestis and Francisella tularensis.

Y. pestis, the agent of plague, produces a cyclic infection of rodents and their fleas in many parts of the world. Maintenance of Y. pestis in nature depends on these rodent–flea–rodent transmission cycles, although it can also be transmitted in some cases by aerosol, direct contact or ingestion (Poland & Barnes, 1979). The disease produces periodic eruptive, rapidly spreading epizootics among certain highly susceptible rodents, followed by regression to focal areas (Barnes, 1982). Historic human plague pandemics exhibit this same pattern. Other species of wild rodents are more resistant to overt disease, and these species are thought to constitute ecologically important reservoir hosts (Kartman et al., 1958). Human plague remains an international public health concern, and recent outbreaks in India and parts of Africa, where the disease had been dormant for decades, suggest a resurgence (Chanteau et al., 1998).

More troubling is the isolation of multi-drug-resistant strains of Y. pestis during the current epidemic in Madagascar (Galimand et al., 1997). These considerations, and the recognized potential of Y. pestis as a bioterrorism agent, underline the need for a detailed understanding of plague transmission and pathogenicity, which hopefully will bring about new effective vaccines and other control measures.

INTRODUCTION

Plant viruses use a variety of mechanisms to enable them to spread away from an initial focus of infection into the wider environment. Many viruses are able to infect the developing seed and so are disseminated to new areas when the seed is shed. In addition, viruses may be taken up, for example by insect pests and fungal pathogens as they feed on or multiply within the plant, and subsequently can be transmitted to further uninfected plants by the vector organism. It is becoming clear that rather than being a non-specific, merely passive process, transmission of plant viruses by vector organisms is a highly specific process, in which particular virus proteins are adapted to allow interaction with the vector.

Two groups of viruses, the tobraviruses and the nepoviruses, use plant-parasitic nematodes as their transmission vector (Taylor & Brown, 1997; MacFarlane et al., 2002). Nematodes are present in almost all environments both on land and in the sea and have many different lifestyles, including parasitism on animals and plants. Over 20 000 species of nematodes are known, of which perhaps 10 % are plant parasites. Considering their diversity it is perhaps surprising that, again, only two groups of nematodes, the trichodorid nematodes and the longidorid nematodes, are responsible for transmitting viruses. Plant-parasitic nematodes in their own right have a considerable impact on agriculture. Worldwide, yield losses attributed to nematode attack have been estimated at 5–12 % per year, although if nematode numbers are allowed to build up by a failure of control practices then yield loss can be far higher (Barker & Koenning, 1998).

THE VIRUS

The influenza viruses are classified in three genera of the family Orthomyxoviridae. The genera are referred to as “types” A, B, and C. The genome, about 14 KB in size, has eight single-stranded RNA segments of negative sense (seven segments in influenza C viruses). The influenza A genome encodes three polymerase proteins (PB1, PB2, and PA); two major surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA); three structural proteins (NP, M1, and M2); and two non-structural proteins involved in nuclear export (NS1 and NS2) (Lamb, 1989). An eleventh open reading frame recently discovered within PB1 appears to code for a protein involved in host cell apoptosis (Chen et al., 2001).

Two surface glycoproteins have been the object of most evolutionary studies of influenza. Hemagglutinin (HA) is involved in binding to host cell surface receptors. Neuraminidase (NA) is necessary for release of daughter virions from host cells. These proteins protrude from the viral envelope and are exposed to host immune defenses. While the HA is the primary target for neutralizing antibodies, antibodies against NA also may reduce occurrence and severity of illness, and possibly prevent infection if present at high titer. The hemagglutinin esterase (HE) in influenza C assumes the functions of both HA and NA. Broad reviews of influenza biology can be found in Murphy and Webster (1996) and Glezen and Couch (1997).

SUBTYPES

Considerable genetic diversity exists among avian influenza A viruses (Webster et al., 1992).

CULTURAL VS. GENETIC EVOLUTION

Human evolution is unique, having developed to the utmost extent a new survival tool: culture. Culture is found in many other animals, but the enormous power of communication made possible by language is not found in any other organism. What do I mean by culture? I like one definition I found in Webster's International Dictionary that I will paraphrase succinctly: the ensemble of knowledge, including customs and technologies, transmitted and accumulated through the generations, that played and continue to play an essential role in the evolution of our behavior. The mechanism of evolution of anything that can be reproduced and transmitted, be it genes or ideas, is dominated by three factors, which were first understood and defined in the study of genetic evolution: mutation, natural selection, and chance (random genetic drift). Although the factors underlying cultural and genetic evolution are very different, the same or similar principles and models are useful in understanding both.

Mutation is transmissible change, of genes or DNA in genetic evolution, and of ideas or brain circuits in cultural evolution. The second and third factors have been loosely described in genetic evolution as survival of the fittest and survival of the luckiest. When we speak of cultural evolution it may seem superficially that natural selection is not involved, i.e., that it is not the environment around us that decides our fate but rather that we take our destiny into our own hands by accepting or rejecting ideas, customs, and habits.

The subject of infectious disease has never before been so intricately linked to our daily lives as it is today. Recent political and social events have underscored the importance of understanding the forces that have shaped, and continue to shape, the evolution of infectious diseases and their underlying genetic basis. The following chapters discuss infectious disease from an evolutionary perspective within the context of the occurrence of genetic polymorphisms in human populations. It was my mentor, J. B. S. Haldane (1949a, 1949b), who first drew attention to the significant role infectious diseases have played in shaping our own evolution.

Haldane's idea was the culmination of long years of investigation into the fundamental nature of evolutionary forces that have shaped the biology of all species on this planet (Haldane 1924, 1932). He was one of the great trio of founding fathers of population genetics, the two others being R. A. Fisher and S. Wright. Haldane and Fisher were also pioneers in human genetics. Haldane contributed quite profoundly to pedigree analysis and gene mapping, as well as to the estimation of mutation rates, selection effects and other branches of human population genetics, and the impact of genetic knowledge on our ethical outlook (Dronamraju 1990, 1995).

In his often-quoted paper, entitled “Disease and Evolution,” Haldane (1949b) wrote: “… the struggle against disease, and particularly infectious disease, has been a very important evolutionary agent, and that some of its results have been rather unlike those of the struggle against natural forces, hunger, and predators, or with members of the same species.