Tag Archives: genetics

Origin of species: through gene regulation?

“How does evolution occur?” This has been a central question in biology. Does evolution occur because a new mutation results in a new protein or because the same gene is regulated differently? How do new morphological structures evolve? How does speciation occur? A recent paper in Science ties principles in evolutionary biology, development biology, and molecular biology to answer these exact questions.

Distalless protein (dll), which is highly conserved across many genera, seems to have EVOLVED A NOVEL FUNCTION in a particular species of insect (Rheumatobates rileyi) to generate male specific antennal appendages. Males possessing these appendages have increased chances of reproducing therefore, have higher fitness (see video below). There could be two reasons for the development of these antennal appendages: first, dll in this particular species is shorter than all other species and second, dll is differentially regulated in this species. Although dll in R. rileyi appears to be shortened,  I feel that its differential expression may be more important in creating this morphology. dll is an important protein in development and therefore, it is pleiotrophic (see figure on the right below). Thus, it is likely that any alteration of the original function by the shortened protein would result in death. One scenario could be that a cis-mediated regulatory change in dll expression causes it to be expressed at a novel developmental stage in a novel tissue where some other male-specific proteins are also expressed. Interactions between dll and such male-specific protein(s) results in the formation of antennal appandages.

So, what does this study tell us about how evolution occurs? Well, one way evolution by natural selection occurs is not through new mutations that alters the function of existing proteins but through mutations that result in modifications in regulation of existing proteins to acquire novel function. Existing proteins may acquire novel functions if they are ectopically expressed, i.e, in developmental stages or tissues where they are normally not expressed. Most of the times ectopic expression may either provide no benefit to the individuals or even be detrimental but sometimes, ectopic expression may allow these proteins to interact with other proteins expressed in that tissue at that developmental stage to perform new functions. This new function may confer some reproductive advantage to that individual, therefore enhancing what population geneticists/evolutionary biologists call ‘fitness’. Over time, these individuals will take over in the population. If this population remains isolated from the ancestral population for a long period of time, it may give rise to a novel species (not this study but can be imagined).

This is a cool example of how integrating many areas of biology (evolutionary, developmental, molecular, and entomology) can elucidate novel genetic mechanisms underlying phenotypic diversity.


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Phylo: Crowdsourcing BIOINFORMATICS and GENOMICS

For many reasons multiple species DNA alignment is a hard problem. One reason it is hard is because as evolutionary relationship between organisms increase, the similarities in their DNA sequence decrease. Many times we encounter gaps and duplications that make accurate alignment very difficult.

Computer algorithms are getting better (compare CLUSTAL-W to  Clustal Omega), it is still pretty darn difficult to accurately align multiple species. A lot of time and effort is needed to manually inspect alignments performed even by the best multiple species aligner. A handful of scientists can only take it so far…so, crowdsourcing helps here.

One can use an algorithm to perform multiple species alignments of multiple genomes. These alignments can then be made publicly available to public such that they can, in their leisure, improve them by manually intervention. Recently, I came across PHYLO which is a GAME, yes a  GAME!!!! in which multiple species alignments of human genome that are potentially linked to various genetic disorders, such as breast cancer can be manually curated by the public. “Every alignment is received, analyzed, and stored in a database, where it will eventually be re-introduced back into the global alignment as an optimization.”

This is a wonderful opportunity for the public to learn a little about bioinformatics and to understand about evolution. So folks, substitute your AngryBirds with Phylo and help yourself increase your chances of living longer by helping the scientific community move closer towards finding ‘cures’ for these diseases.

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Mapping Human Brain:An awesome video at TED

This was an awesome presentation demonstrating appication of genomics to understand human biology. This would be wonderful to educate general public and high school students about the following:

  1. Biological systems are very complex: thousands of genes produce thousands of proteins at various times that mediate billions of neuronal interactions. Genomics tools (microarray: the things with green dots in this talk)
  2.  A lot of work and time is needed to learn fundamentals of biology: many scientists are needed to gather biological specimen, perform experiments, and to analyze data. In this video only 2 brains were used. Imagine using hundreds of tissues.
  3. Integration of computer programming in visualization: today, because of genomics massive amount of data can be generated in little time. However, in order to analyze and understand the data, computational tools are needed. Once the data is analyzed, computer graphics is needed to visualize the data (the brain with nice colors in this talk). Therefore, computational biologists and artists are becoming important components of the genomics community.
  4. Applications of such studies: Once we accumulate many such studies, they can be used to design drugs or to prevent a disease in general population. This takes even more time and resources.

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Could Rautes, Kusundas, Chepangs, Rajis or Tharus be the first peoples to colonize the Himalayas 7000 years ago?

Rautes: The last nomads of Nepal

This picture belongs to Kishore K. Sharma, an awesome Nepali photographer. Please do visit his blog by clicking on this picture to view more pictures of the Rautes.

History of Nepal, as taught in academic institutions, starts with Gopalavamshis, the so-called first rulers of Nepal, followed by Mahispalavamshis, Kiratis, Licchavis, Mallas, and Shahs in that order. However it only represents the political history of Nepal at its best. To understand history of Nepal in its completeness, one must learn about the history of the peoples of Nepal.

Human inhabitation of the Himalayan foothills, known as present day Nepal, predates the dawn of civilization and the Gopalavamshis because prehistoric stone tools of “Patu industry,” a non-agricultural Mesothilic culture unique to Nepal were recovered in Central Nepal[1]. Two distinct types of tools, the Patu tools resembling the 10-12 thousand years old Hoabinhian culture and another resembling 10-30 thousand years old culture in India highlight three important points about ancient Nepali history: first, modern day Nepal has been inhabited by humans since the Pleistocene; second, Nepal has been cosmopolitan even in the Mesolithic harboring Indian and South East Asian cultures, and finally, the Patu people had an unique cultural identity by the Mesolithic.

But what happened to the Patu people? It is curious that a few nomadic hunter-gatherer tribes live/until recently lived the Mesolithic lifestyle in central Nepal, where the “Patu industry” once existed. Could they be the descendants of the Mesothilic humans that developed the first Himalayan culture?

Kusundas (aka Myahak, Ban Rajas) and Chepangs (aka Prajas) are one of the highly marginalized tribes in Nepal. Until a few decades ago both these tribes were nomadic hunter-gatherers. With forests gone, Kusundas were forced to desert their nomadic life and enter villages, which caused annihilation of their culture, traditions, and languages. Only a few Kusundas today, speak their native language. Like the Kusundas, Chepangs were also nomadic hunters and gatherers in central Nepal. Destruction of forests has forced Chepangs to adopt a semi-nomadic life in the non-yielding slopes of the Mahabharat range.

In addition to their hunter-gatherer lifestyles, linguistic and anthropological evidence suggest that Kusundas and Chepangs have been living in central Nepal since ancient times. Both the Kusundas and the Chepangs were officially first reported by B.H. Hodgson, a British naturalist and ethnologist in mid-nineteenth century, as “broken tribes” living nearly “in a state of nature” and carrying bows and arrows with no relationship with the rest of the “civilized races” of the country[2]. Later CJF Forbes found more plausible relationship between Chepangs and Khyens (Kiiyen) and Kumis of Arakan hills in Burma (Myanmar) and even concluded that Chepangs may have entered Nepal from the east [3]. Unlike Chepang, Kusunda language is difficult to classify as it similarities with various unrelated language groups such as Austro-Asiatic (Munda)[4], Tibeto-Burman, and even Indo-Pacific[5]. It is now widely recognized as a language isolate[6]: a language distinct from all other languages spoken in Nepal.

Although both Chepang and Kusunda languages seem to be unrelated to any other languages in Nepal, they appear to be linguistically closely related to each other (see Figure1). It is plausible that Chepangs and Kusundas have cohabited the Mahabharata hills and centuries of linguistic exchange may have resulted in their language similarities. Furthermore, anthropological evidence seems to corroborate the linguistic antiquity between these tribes, for example, both the Kusundas and the Chepangs have a folk legend according to which the Kusundas are the descendants of Kusa (thus the name Kusunda) and Chepangs are the descendants of Lava, both the sons of Rama and Sita of the Ramayana. Furthermore, interviews with Chepang traditional healers and medicine men revealed hundreds of plants used for diverse purposes and many of them were previously not documented.[7] The tremendous ethno-botanical knowledge of the Chepangs further substantiates their occupation of central Himalayas since ancient times for such knowledge of local flora can only be built with time. Hence, Kusundas and Chepangs, by virtue of their nomadic life styles and lack of linguistic affinities with any other languages of Nepal, may have inhabited the Himalayan foothills long before other ethnicities emigrated.

Recently, genomics has been used to infer the demographic histories of human populations throughout the world. Analysis of Kusunda genome in a recent issue of Science[8] supports some of the linguistic evidence and indicates that Kusundas are related to Tibeto-Burman speaking North East-Asian populations such as Hezhens, Oroqens and Mongolians but are not related to the Australian or Papuan Aborigines and virtually unrelated to any of the human populations from East or South Asia. Remarkably, a Kusunda specific genetic component is evident; however, without further analysis it is difficult to determine whether this component is due to long period of population isolation or due to ancient age of the population.

Genetic and linguistic evidence argues that Kusundas are possibly the most ancient of Nepali populations. They , may have come into contact with Mundas and Burmese in Eastern Himalayan foothills in ancient times. Words burrowed from these languages may have remained in Kusunda language to date. However, more work is needed to determine whether the Kusunda specific genetic components are a result of recent inbreeding due to population isolation or whether they are archaic genome components due to Kusundas’ antiquity in the Himalayan foothills.

Although it is tempting to crown Kusundas as the eldest peoples of Nepal, other nomadic/semi-nomadic tribes of central Nepal cannot be ignored. Genetic analysis of Chepangs may show that they have also cohabited the Mahabharata hills for centuries. It is also noteworthy that many other tribes along with Kusundas and Chepangs may have inhabited central Nepal since ancient times. For example, the Tharus may be descendants of inhabitants of the Terai since the Paleolithic. Tremendous ethnic and cultural diversity within Tharus that spread throughout the Terai region attest their occupation of the land for centuries. However, it is interesting that there is little linguistic similarity between the Tharus and the hunter-gatherers of central Nepal suggesting that there may have been very little interactions between the populations of the hills and that of the plains. Furthermore, Rautes that are still nomadic and Rajis that recently gave up nomadic lifestyle may have resided in central Nepal before the advent of agriculture. Many more ethnicities of Nepal may have inhabited the Himalayan foothills since ancient times but little is known about them. Hence, it is really important to investigate the history of all the peoples of Nepal for accurate presentation of Nepali history and their origins as such studies are also interesting from the perspectives of human evolution. Himalayas are believed to have acted as a barrier for gene flow between the Indian subcontinent and Central Asia. However, the fertile Himalayan foothills with diverse flora and fauna may have been a Mesolithic melting pot for migrants from both the sides of the Himalayas since Mesolithic times. Understanding the origins and demographic histories of present tribes of Nepal may reveal novel aspects of ancient human dynamics in Asia.

In summary, there is abundant evidence that present day Nepal was inhabited by humans since the Paleolithic and a culture unique to Nepal existed by Mesolithic. It is possible that hunter-gatherer populations currently residing in central Nepal, such as Kusundas, Chepangs, Rautes, and Rajis may be the descendents of the Patu people that developed the first culture of Nepal some 7000 years ago. There is a dire need for additional archeological, anthropological, linguistic, and genomic studies to understand the ancient history of Nepal accurately.

[2] Hodgson, B. H. (1848) J. Asiat. Soc. Bengal 17 , 73–78

[3] Forbes, C. J. F. (1877) Journal of the Royal Asiatic Society of Great Britain and Ireland, New Series, Vol. 9,No. 2,  pp. 421-424

[4] Reinhard, J. & Toba, T. (1970) A Preliminary Linguistic Analysis and Vocabulary of the Kusunda Language (Summer Institute of Linguistics, Kirtipur, Nepal).

[5] Whitehouse et al. (2004) Kusunda: An Indo-Pacific language in Nepal. PNAS Vol. 101,No. 15, pp. 5692-5695

[6] Watters, D. (2005) Notes on Kusunda grammar (a language isolate of Nepal). Kathmandu: National Foundation for the Development of Indigenous Nationalities.

[7] Rijal A. 2011. Surviving on knowledge: ethnobotany of Chepang community from midhills of Nepal. Ethnobotany Res Appl 9:181-215.

[8] Rasmussen, M. et al. (2011) An Aboriginal Australian Genome Reveals Separate Human Dispersals into Asia. Science Vol. 334, No. 6052, pp.94-98


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Regulatory elements and the complexity of identifying them

Gene Regulation
Img Src: Berger SL. 2000 Nature (doi:10.1038/35044160)

Understanding genetic variations that govern morphological differences is important in understanding the evolution of species (1). Although understanding mechanisms of gene regulation driving morphological differences is interesting, important, and necessary, it is incredibly difficult to investigate regulatory mechanisms because they are complex. First, body plans and body parts are highly complex and many genetic factors are responsible in development of body parts. Also, not all morphological differences are due to the same genetic mechanism. In this paper I will point out some of the problems in identifying genetic mechanisms governing morphological variations and discuss a few instances where regulatory elements have been identified.

Genetic factors regulating morphological differences
There are three potential mechanisms that can drive morphological differences. They are changes due to variation in coding regions of a gene resulting in a dysfunctional protein, variation in trans-regulatory proteins, and variations in cis-regulatory elements. It was clear by early 1970s that proteins may not explain most of the morphological differences. Based on various reports investigating polymorphisms in protein coding regions between humans and chimpanzee, Wilson and King concluded that regulatory elements and not proteins may be responsible for morphological variations (2).

Components of Regulatory System
Regulatory mechanisms have two components: trans-regulatory elements (TRE) and cis- regulatory elements (CRE). The scientific community is divided regarding which of the two contributes most to the morphological divergence. Some argue that although CRE have some role in evolution, biological processes such as speciation and adaptation are facilitated mostly by structural mutations (3, 4). It has been shown that a change in one amino acid can cause morphological changes such as coat color variation in mice (5). Many more examples of structural mutations contributing to morphological differences are discussed in ref.(4). There is also plenty of evidence that CRE can mediate morphological variations and many are summarized in ref.(6).

Cis- and trans-mediators both regulate morphological changes
Even though there are compelling evidence that both cis and trans regulatory changes can drive morphological differences, cis mediated changes seems to have gained momentum over trans mediated changes. This is because of at least two reasons. The first is due to the structural differencs between the two regulatory elements. CRE are non-coding, non-pleiotropic with spatial and temporal function, and modular (7, 8). Since they are non-coding, they can sustain more mutations than structural proteins. Unlike proteins (especially transcription factors that mediate trans-regulation) that have more than one function, CRE are non-pleiotropic thus any mutation sustained by CRE probably influences only one particular trait which unless deleterious does not affect the overall fitness of an organism. Thus CRE can accumulate mutations these mutations can produce changes that can be selected for. Finally, CRE are modular and one or a few mutations in various modules may not affect its overall function (9).

On the other hand, although proteins have spatial and temporal expression, they are pleiotropic and a change in a protein can make it dysfunctional. If the protein is involved in more than one pathway, then all the pathways are dysfunctional and this has a major impact in the fitness of the organism. Hence the argument is that proteins may not be the major contributors in driving morphological variations. However, this conclusion is influenced by current findings that show not many proteins are different between two species but the caveat here is how difference is defined. Most studies have investigated changes in nucleotide or amino acid sequences of coding regions but changes due to post transcriptional modifications such as splice variants are not fully investigated. It is possible that different splice variants function differently. Furthermore, the conclusion that only CRE and not trans-regulatory proteins mediate morphological variation is not entirely true as some studies have shown that changes in proteins can mediate morphological variations (5). Finally, it has been shown that proteins can be modular sustaining many changes in the amino acid level that has enabled them to retain their ancestral function at the same time gain novel functions (10).

Identifying regulatory elements
Even though it is likely that both CRE and TRE play a role in driving morphological differences, it is really hard to identify either of the regulatory elements. Finding TRE is harder because it can be anywhere in the genome whereas finding CRE is relatively easier because it is somewhere in that particular chromosome. Also, trans-regulatory networks can be huge consisting of thousands of proteins and hundreds of pathways and we are just beginning to understand the interconnection of such proteins in such networks. Therefore, it is not hard to imagine that finding a TRE that can be anywhere within the abyss of a regulatory network is next to impossible. While finding trans-regulatory elements is harder, finding CRE should be a simple straightforward task because by definition, CRE is defined as “a segment of DNA that regulates transcription; such segments typically lie immediately 5′ of the start site of transcription, but are often discontinuous, and individual segments can reside within introns, 5′ and 3′ UTRs, or tens of kilobases on either side of the gene they regulate” (6). However, finding CRE is also not that easy because the very properties of CRE (non-coding, non-pleiotropic, and modular) make them difficult to find. To elucidate the difficulties in identifying CRE, I will focus on recent reports on three morphological traits (pigmentation and hair structure in flies and pelvic structure in stickleback fish).

CRE that regulates abdominal pigmentation in Drosophila
Jeong et al. investigated what appears to be a simple morphological trait: the difference in male specific black pigmentation in abdomen of two Drosophila sister species that diverged recently; between 0.15-0.5 Mya (11). D. yakuba flies show the male specific pigmentation pattern but D. santomea flies lack the black pigmentation in their abdomen. These flies are geographically distributed in close by areas with D. yakuba found in lower altitudes where as D. santomea found in higher altitudes in an island in West Africa (12).

The authors seem to have chosen this particular morphological difference because of two reasons. First, they had extensive knowledge of the genetic mechanism regulating abdomen pigmentation in various Drosophila species including D. santomea because they had previously demonstrated that a pigment associated gene called yellow in the X chromosome, which is regulated by ABD-B Hox gene, plays a role in pigmentation in many Drosophila species (13, 14). Second, Carbone et al. had previously shown that four loci acting as QTL with large effect are responsible for the intra-species differences in abdomen pigmentation between D. yakuba and D. santomea (15). Of these four QTL two were in X chromosomes. From their previous work, which included D. santomea, they had observed that none of the mechanisms shared by other Drosophila species seem to play a role in lack of pigmentation in D. santomea indicating that a novel mechanism must be responsible for the colorless phenotype in D. santomea. It was also known that another gene tan is also involved in abdominal pigmentation. Both genes regulate the black melanin pigmentation in the abdomen and lack of tan causes severe under pigmentation. Naturally, tan was suspected to be responsible for loss of pigmentation in D. santomea.

Despite the intensive knowledge of pigmentation in flies, Jeong et al. had to perform multiple crosses, construct multiple transgenic constructs to measure gene expression, and make transgenic flies with these and additional constructs to show that of the four QTL found by Carbone et al. (15), the major QTL is the tan gene on X chromosome. This demonstrates that the same phenotype can be governed by multiple mechanisms and even if the mechanism that governs a morphological variation is well characterized in one species, this same mechanism may not be responsible for the same variation in another despite they are closely related. This shows the complexity of identifying CRE responsible for morphological variations.

To show that the lack of pigmentation in D. sanomea is not due to dysfunctional tan protein and not due to trans mediated elements the authors had to perform another series of crosses, conduct sequencing, and make additional transgenic flies. Fortunately, tan transcription unit in D. melanogaster was already known which enabled them to investigate for the CRE in the transcription unit of D. melanogaster (16). After finding the CRE in melanogster they had to repeat their experiments in D. santomea. They made transgenic D. santomea flies with the CRE of D. melanogaster and observed restoration of pigmentation in D. santomea concluding that CRE in tan is responsible for lack of pigmentation in D. santomea. In a sense they were fortunate possibly due to short divergent time between these two species that the D. santomea TRE was able to recognize the CRE from D. melanogaster, which enabled the restoration of pigmentation upon addition of functional CRE. Interspecies CRE may not necessarily restore function as some transcription factors may have also changed since two species have diverged (melanogaster and erecta in ref. 9).

Although Jeong et al. demonstrate that CRE in tan is responsible for pigmentation, they were not able to identify the differences within the CRE that may be responsible for pigment loss in D. santomea. After aligning the CRE sequences from many members of D. santomea and many other Drosophila species they found that there were more variations within species than between species. This demonstrates the complexity of pinpointing the changes within a CRE even after it is identified. Also, it is important to acknowledge the Drosophila genome is compact. Identifying the CREs in humans may be even more complicated due to tremendously large human genome full of repeats.

CRE that regulates trichome patches in Drosophila
The complexity of identifying mechanisms of another morphological trait, differences in trichome patches in various species of Drosophila, was demonstrated by Sucena and Stern (17, 18) and McGregor et al. (17, 18) in two papers published seven years apart. They compared abdominal hair patterns in five Drosophila species and picked two closely related Drosophila species one of which has hairy abdomen (D. simulans) and the other has bald abdomen (D. sechellia) for further experiments. Using crosses rather than molecular biology techniques used by Jeong et al to map the CRE, they showed that the regulation of hair development in flies maps to a region in X chromosome near the ovo/shaven-baby (ovo/svb) gene (17). Seven years later McGregor et al. was able to locate the enhancer regions that regulate differences between two Drosophlila species and they also come up with a robust possible model of evolutionary path for hairlessness in D. sechellia (18).

CRE that regulates pelvis modification in freshwater sticklebacks
All of the above mentioned studies demonstrate complexity of identifying genetic factors that regulate morphological variations in Drosophila. However, the complexity of variation is not unique to flies and this mechanism is at least equally complex in vertebrates as demonstrated by pelvic structure in stickleback fish. Marine stickleback fish have pelvic spines that protect them from predators. These spines are absent in freshwater fish. Shapiro et al. investigated the genetic mechanism that control pelvic reduction by performing crosses between the freshwater and marine fish followed by myriad of molecular biology techniques including QTL mapping, sequencing, RT-PCR, and in-situ hybridization (19). Their QTL mapping results indicated that there are multiple genes that are involved in pelvic modification in sticklebacks of which Pitx1 seemed the most important. Like Carbone et al (15), Shapiro et al also found that more than one genetic factor is responsible in controlling morphological trait. Furthermore, Pitx1 and other QTL discovered in this study were different from that previously reported by the same group indicating that more than one mechanism may be involved in spine formation in these fish (20).

Like Drosophila regulatory mechanism in stickleback is complex and despite patiently performing many complicated experiments, the best Shapiro et al could do was to identify the genetic region responsible for pelvis modification but not identify it. They did show that the no changes in the coding regions of the Pitx1existed and that the protein assembled properly and maintained proper spatial expression in freshwater fish that lacked the spine. It took them another six years to identify the exact location of the CRE mediating the pelvis structure which was found in enhancer region of Pitx1 gene reintroducing which restored the pelvic spine (21). Similar to Jeong et al., they found that there were multiple deletions within the enhancer region of Pitx1 in freshwater fish from various geographical areas demonstrating that the loss of pelvic spine has occurred independently and multiple times in the evolutionary past. Also, similar to D. santomea, the trans network must have remained preserved in the stickleback to allow for spine restoration upon introduction of the functional CRE. This demonstrates that even in the absence of CRE, trans-regulatory network preserve their function, whether this is due to preservation of ancestral function despite acquiring novel ones remains unclear.

It takes a lot of time, patience, and money among other things to perform such comprehensive studies to elucidate mechanisms of gene regulation governing morphological variations. The lesson that we can learn from these studies is not whether CRE or TRE drive evolutionary changes but how complex regulatory systems are. The studies mentioned above are commendable in that despite tremendous difficulties they have shed light on some of the most complex genetic mechanisms. With advent of novel molecular biology tools hopefully more studies of such kind will unravel more of the hidden genetic factors that control gene regulation. Possibly computational tools can be developed to investigate the cryptic regulatory elements in the genome. The long journey of understanding gene regulation lies ahead and investigating both cis and trans components of gene regulation will elucidate major mechanisms that drive evolutionary processes.

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