Collection of Title of Dissertation

A Comprehensive Collection of Title of Dissertations Submitted by Students of M. Sc. Microbiology, Tribhuvan University till 2004 A.D

1. Microbial quality of fruits of Kathmandu Valley and their utilization in wine making and upgrading protein contents of fruits’ peels by using Aspergillus niger, Trichoderma reesei andPenicillium spp. By: RajanPrasad Adhikari

2. Study of Campylobacter in diarrhoeal and non-diarrhoeal Nepalese children and detection of Rotavirus in diarrhoeal children. By: Bidya Shrestha

3. Bacteriological investigation on ice-cream of Kathmandu Valley. By: Anjana Maharjan

4. Study on the water pollution of Ranipokhari and use of fish culture as a biological control of pond pollution. By: Anjana Shrestha

5. Study of microbiology and chemistry of Kinema. By: Kedar G.C.

6. Study of physical composition and bacteriological analysis of solid waste of Kathmandy city. By: Shova Shrestha

7. Isolation and characterization of thermophilic and amylase positive bacteria from hot spring of Nepal. By: Dwij Raj Bhatta

8. Biotyping of coagulase negative staphylococci (CONS). By: Predeep Kumar Shah

9. Bacteriological study of food and water of Pode community of Kirtipur. By: Pearl Banmali

10. Epidemiology and microbiology of lower respiratory tract infection among patients in Nepal. By: Bimmi Shrestha

11. Bacteriological study of chicken and buff meat of Kathmandu Valley. By: Gyanendra Bdr. Karki

12. Preliminary survey of dominant bacterial flora of indoor air of Kathmandu. By: Indu Bikram Joshi

13. Proteolytic activities of mesophilic bacteria. By: Anjuman Shrestha

14. Study of the lipolytic activities of fungi isolated from different oil mill areas. By: Sangita Shakya

15. Prevalence of bacteriuria and UTI in Nepali women. By: Prakash Ghimire

16. The study of antimicrobial resistance Escherichia coli. By: Dev K Ranjit

17. Study of solid waste of Kathmandu Valley and its impact on Kathmandu. By: Buddhi Pudasaini

18. Microbiology of wound infection, a hospital based study. By: Moti Lal Shrestha

19. Bacteriological profile of bacteremia and septicemia among patients visiting Patan Hospital. By: Durga Ghimire

20. Bacteriological study of cheese of Kathmandu city. By: Ira Tuladhar

21. Serological analysis of Escherichia coli isolated from various clinical specimens with special interest in gastroenteritis. By: Bishwakala Aryal

22. Microbiology of wound infection at Tribhuvan University Teaching Hospital. By: Sabina Dangol

23. A research on integrated fish culture utilizing human wastes in Nepal. By: Rabindra Acharya

24. Bacteriological study of ice-cream, butter and Raspherry of Kathmandu city. By: Pradipata Udash

25. Improvement of nutritional value of soybean by fermentation using Aspergillus oryzae. By: Pravin Malla Shrestha

26. Microbiological study of paper industries influent. By: Amod K. Pokherel

27. Screening of thermophiles from hot spring of Nepal for thermostable proteases. By: Binesh Shrestha

28. The study on microflora of fish pond water and fish intestine. By: Kushmabati Shrestha

29. HACCP module for traditional meat based street foods of Nepal. By: Lisha Joshi

30. Microbiology of urinary tract infection: a hospital based study. By: Sagarika Manandhar

31. Isolation of pectolytic microorganisms from citrus fruits and characterization of their pectic enzymes. By: Sarita Manandhar

32. Fermented soybean, a possible replacer of fish meal. By: Rashmila Prajapati

33. Isolation of Bacillus thuringiensis from soil of Nepal and its insect toxicity. By: Rina Pradhan

34. Bacteriological study of fresh vegetables of Kathmandu Valley. By: Paru Joshi

35. Isolation of Salmonella spp from blood and study of its antibiotic sensitivity pattern. By: Basudha Shrestha

36. Study of different diagnostic methods and prevalence of pulmonary tuberculosis among Nepalese population. By: Chandra Prakash Bhatta

37. Hazard Analysis Critical Control Point process in milk chain. By: Deen B. Bhatta

38. Studies on amylolytic activity during solid state fermentation of Murcha, a traditional yeast starter of Nepal. By: Gyanendra Ghimire

39. Bacteriological study of water and its treatment using plant product. By: Manoj Thapa

40. Serological survey of Hepatitis B surface antigen among the healthy Nepalese males. By: Kishor Manandhar

41. Microbiological study of body fluid. By: Sarala Joshi

42. Fermented soybean suitable protein source in fish diet in relation to its enzyme system. By: Rakesh Kumar Jha

43. Study on beta lactamase activity by microbiological and biochemical methods inStaphylococcus aureus isolated from healthy nasal carriers and hospital isolates. By: Ira Shrestha

44. Study of aetiology of acute diarrhea with special different hospitals. By: Chandana Gurung

45. Microbial analysis of burn injuries at burn unit of different hospitals. By: Manju Shree Shakya

46. Study of air microflora of Kathmandu Valley and its seasonal and locational variation. By: Babu K. Sharma Kuikel

47. Microbiology and chemical analysis of food beverages (alcoholic and non-alcoholic) at Kathmandu Valley. By: Bikash Pandey

48. Nutritional improvement of soybean by fermentation for its possible use in feed for developing state of carp family. By: Rajeev Mani Nepal

49. Bacteriological analysis of fish and its environment and enzymatic activities of fish isolates. By: Puspha Man Shrestha

50. Isolation of antibiotic resistant enteric bacteria from community ponds and their antibiotic transfer mechanism in such environment. By: Kalpana K.C.

51. Optimization of nutrient conditions for thermostable protease production. By: Sushil Man Singh Pradhan

52. Hazard analysis critical control point (HACCP) process of cheese manufacturing in Nepal. By: Rishi Prakash Niraula

53. Study on industrial effluent and its biological treatment using LEMNA species. By: Binod Lekhak

54. Characterization and optimization of alpha amylase produced. By: Sampurna S. Dangol

55. Microbiology of burn wound in children at Kanti Children’s Hospital. By: Leela Shrestha

56. Prevalence of urinary tract infection on children. By: Kirtika Gautam

57. Studies on mesophilic and thermophilic microorganisms commonly found in compost piles of Kathmandu Valley. By: Rumu Amatya

58. An epidemiological study of antibiotic resistant enteric bacteria in sub-community of Kathmandu Valley. y: Bishnu Raj Tiwari

59. Microbiology of oral cavity with special interest to beta haemolytic Streptococcus. By: Anjana Shakya

60. Characterization of E coli isolated from urinary tract infected patients. By: Kiran Shah

61. Study of causative organisms from pus sample and its antibiotic sensitivity pattern. By: Keshab Parajuli

62. Study of antimicrobial properties of Punica granatum linn By: Luna Bhatta

63. Assessment of ground water quality and study of antibiotic resistance and oligodynamic action against some isolated enteric bacteria. By: Makhan Maharjan

64. Antibacterial activities of actinomycetes isolated from soils of Kathmandu Valley. By: Reshma Tamrakar

65. Impact of effluents on rivers and reduction of biochemical oxygen demand usingCladosporium oxysporium. By: Sunil Manandhar

66. Cervicitis and cancer of cervix in Nepal. By: Archana Shrestha

67. A prospective study on bacteriology of lower respiratory tract infection among the patients visiting T.U. Teaching Hospital, Kathmandu. By: Kaushal Joshi

68. Study on urinary tract infection and cancer of urinary bladder. By: Jyoti Amatya

69. Infection of foot ulcers in leprosy patients. By: Krishna Lal Kandel

70. A prospective study on bacteriology of wound infection among inpatient at Bir Hospital (a hospital based study). By: Archana Katuwal

71. A prospective study of etiological agents causing infective endocarditis and related bacteremic and septicaemic cases among patients visiting Bir Hospital. By: Anjali Tibrewal

72. Prospective study on aetiology of childhood diarrhea based on clinical features and laboratory investigation. By: Hirdaya Ratna Shakya

73. Seroprevalence of Hepatitis B and Hepatitis C infection among blood donor in Kathmandu Valley. By: Monika Joshi

74. Utilization of fruit wastes for the production of citric acid via fermentation by usingAspergillus niger. By: Pushpa Raj Dahal

75. Utilization of tea wastes as a substrate for microbial protein production. By: Buddhi Sagar Ghimire

76. Production of aflatoxin by Aspergillus flavus isolated from different edible food stuffs of Kathmandu. By: Rupa Acharya

77. Antibacterial activity of actinomycetes isolated from various geographical region of Nepal and characterization of their antibacterial agents. By: Deepak Singh

78. A prospective study of urinary tract infection based on culture and direct microscopy of urine along with the antibiotic sensitivity test of urinary pathogens. By: Bijaya Kumar Dhakal

79. Insecticidal activities and immunology of delta endotoxins of Bacillus thuringiensis isolated from insect samples of Nepal. By: Krishna Pd. Subedi

80. Preliminary test of bacteriiocins from Pseudomonas spp isolated from potato. By: Roshana Joshi

81. Isolation, screening, identification and selection of best fermentative yeast from Murcha sample. By: Sandesh Regmi

82. Prevalence of acute diarrhoeal episodes in Kathmandu Valley during 1997. By: Aarati Karki

83. The isolation and identification of antibiotic producing bacteria in the compost samples of Kathmandu Valley. By: Pallavi Sthapit

84. Studies on effect of pesticides on soil inhabiting bacteria of pesticide applied cultivated fields of Kathmandu Valley. By: Shaila Basnyat

85. A prospective study on bacteriology of wound infection at T.U. Teaching Hospital. By: Palpasa Tuladhar

86. Study of Methicillin resistant Staphylococcus aureus (MRSA) isolated from different clinical samples. By: Reena Lamichhane

87. Fermentation of grape juice by using brewing yeast isolated from Nepalese starter Murcha. By: Chenu Gangal

88. Efficacy of alcohol fermentation of Hordeum vulgare (naked barley) from traditional Murcha. By: Leena Rajbhandari

89. Antibacterial activity of natural honey: a preliminary study. By: Sanchita Sapkota

90. Drug resistant enteric bacteria in poultry samples of Kathmandu Valley and their epidemiological study by plasmid profiling. By: Thakur Pd. Paude.

91. Screening of aflatoxin producing Aspergillus flavus isolated from maize and study on their growth suppression by various chemical agent. By: Harish C Shrestha

92. A prospective study on aetiology of bacteraemia, septicaemia at Tribhuvan University Teaching Hospital. By: Nawa Raj Banjade

93. A prospective study on aetiological agents of diarrhoeal disease in children in relation to parasites and to determine the antibiotic sensitivity pattern of isolates. By: Anand Bd. Chand

94. A study on sexually transmitted infections among the patients visiting at Tribhuvan University Teaching Hospital. By: Binita Panta

95. A study on diarrhea in children in relation to behavioral and environmental factors. By: Sujan Piya

96. Studies on role of exopolysaccharide of Xanthomonas campestris PV.Campestris, isolated from cabbage seeds, in pathogenesis and correlation of exopolysaccharide in pathogenicity on host plants. By: Dev Raj Joshi

97. Prevalence of multi drug resistant enteric bacterial pathogens in diarrhoeal patients of Kathmandu and study of their relatedness by plasmid profiling. By: Abhignya Subedi

98. Study on relationship between the infection of Helicobacter pylori and Epstein Barr Virus and the carcinogenesis of the gastric cancer. By: Priyamvada Paudyal

99. A prospective study on antibiotic sensitivity profiles of the organisms associated with clinical infections among the patients attending T.U. Teaching Hospital: a hospital based study. By: Chandra Kala Rai

100. Antibiotic resistant Vibrio cholerae isolated from Kathmandu Valley and characterization of the isolates by biotyping and serotyping. By: Arishma Rajkarnikar

101. Microbiological and chemical analysis of mineral water sold in the Kathmandu Valley. By: Shiva Raj Pohkare.l

102. Screening and evaluation of the antimicrobial activity of some medicinal plants of Nepal and isolation of pure antimicrobial compound from Bauhinia variegatn. By: Naba Raj Pokhrel

103. Microbiology study of street fried foods and isolation and identification of some microorganisms of public health importance. By: Pankaj Acharya

104. Microbiological study of raw meat of Kathmandu Valley with public health and veterinary importance and serological study of the isolated Salmonelas spp. By: Purushotam Prasai

105. Serodiagnosis of syphilis among clinically suspected patients visiting Bir Hospital and the risk of HIV and Hepatitis B infection among syphilitic patients. By: Sunita Pokhrel

106. Bacterial analysis of street food in relation to child health. By: MunMun K.C.

107. Immunodiagnostic for tuberculosis. By: Bhupesh Khadka

108. Antimicrobial activity of essential oils of some common spices. By: Sapan Sharma

109. Study on viruses in relation with skin cancer among Nepalese people. By: Rajindra Pd. Aryal

110. Study on cytokine (interferon-gammee) responses to skin test antigens of leprosy. By: Parmeshwar N. Amatya

111. Bacteriology of ear discharges. By: Charu Aryal

112. Study of solar disinfection of drinking water. By: Pratap Karki

113. A study of severe malaria in relation to HIV and syphilis among patients visiting Bheri Zonal Hospital. By: Prakriti Raj Kandel

114. Study of prevalence of Helicobacter pylori in gastroduodenal diseases and evaluation of antibiotic sensitivity pattern of the isolates. By: Suresh Subedi

115. Monitoring of liver and renal function among human immunodeficiency virus positive individuals. By: Abhilasha Karki

116. Study on bacterial flora in blood specimen collected from hospitalized and out patients services of Tribhuvan University Teaching Hospital. By: Rupa Shakya

117. Sero diagnosis of Japanese encephalitis and malaria and an assessment of public health awareness about the above (a study diseases confined within Bheri Zonal Hospital). By: Prerana Bajracharya

118. Study of physio-chemical and bactgeriological parameters of Bagmati river and treatment of polluted water using Cladosporium resinae. By: Prakash Paudyal

119. Prevalence of tuberculosis among the suspected patients visiting Tribhuvan University Teaching Hospital and their antimicrobial resistance pattern. By: Ganga G.C

120. Study of indoor Vs outdoor air microflora and its relation to PM7.07 By: Arjun Thapa

121. Air quality assessment of brick kiln area. By: Giri Raj Dahal

122. Study of microflora of vermicompost and its antagonistic activity against plant pathogenic bacteria. By: Shila Bhattarai

123. Determination of antibiotic resistant Gram negative urinary pathogens in pediatric patient at Kanti Children’s Hospital. By: Safala Dhital

124. Prevalence of common bacterial pathogens in different clinical samples submitted at Tribhuvan University Teaching Hospital and their antibiotic sensitivity test profiles. By: Rama Dhungel

125. Screening and evaluation of in vitro antimicrobial activity of medicinal plants of Nepal. By: Mahesh N. Baidya

126. Enumeration and isolation of pesticide degrading bacteria from different soil samples of Kathmandu Valley and study on transrerability of degradative plasmid from Pseudomonas putida isolates into E coli. By: Anju Sharma

127. Study of Hazard analysis critical control points (HACCP) system in sausage production plants. By: Buddhi K Shrestha

128. Study of microbial flora present in the conjunctiva of the cataract patients before and after the use of betadine solution and its antibiotic sensitivity pattern. By: Lata Ghimire

129. Study of microbiological and chemical quality of fermented milk (DAHI) of Kathmandu Valley. By: Sushama Sharma

130. Distribution of citrus tristeza virus (CTV) in various regions in Nepal and development of virus free plantlets by meristem culture. By: Chaman Ranjit

131. Antibiotic sensitivity profile of E coli, Klebsiella spp and Pseudomonas spp of patients visiting TUTH, Kathmandu. By: Tarani Prasad Paneru

132. Study of air, water and wound infection in different wards of T.U. Teaching Hospital. By: Megh Raj Banjara

133. Insecticidal activities of Bacillus thuringiensis against Culex quinquefasciatus andSpodoptera litura. By: Sangita Bhattarai

134. Study of meningitis in patients visiting Tribhuvan University Teaching Hospital. By: Kiran Babu Tiwari

135. Microbial digestion of vegetables and kitchen wastes for biogas production. By: Nawa Raj Dhakal

136. Development of IND-ELISA for actinomycetes and study of serological relationship. By: Yogan Khatri

137. Assessment of drinking water quality supplied by Nepal water supply corporation, Sundarighat and identification, antibiotic sensitivity pattern and serotyping of isolated E coli. By: Supriti Shrestha

138. Pattern of microbial flora among the visitors and the environment of intensive care unit (ICU), Tribhuvan University Teaching Hospital. By: Sriju Sharma

139. Prevalence and antibiotic sensitivity pattern of Methicillin resistant S aureus (MRSA) in Bir Hospital. By: Rajita Rajbhandari

140. Salmonella serotyping and drug susceptibility pattern from envirionment and clinical samples of urban Nepal. By:Aashish Poudyal

141. Bacteriological study of upper respiratory tract infection inpediatric patients at Kanti Children’s Hospital. By: Anima Shrestha

142. A hospital based study of urinary tract infection among women visiting antenatal clinic of Tribhuvan University Teaching Hospital. By: Rupa Pandey

143. Drinking water quality assessment of Kathmandu Valley and antibacterial property of enteric bacteria isolated. By: Tista Prasai

144. Prevalence of beta haemolytic streptococci in throat of school children and its antibiotic sensitivity pattern. By: Deepak Acharya

145. Study on nasal carriage of Staphylococcus aureus among the post operative ward visitors, staff and patients of T. U. Teaching Hospital with drug sensitivity pattern. By: Khadga B. Shah

146. Optimization and use of polymerase chain reaction for the diagnosis of tuberculosis and leprosy. By: Bishwa Raj Sapkota

147. Prevalence of bacterial infection in acute hepatitis in Nepal. By: Durga Shrestha

148. Quality control in tuberculosis smear microscopy. By: Sneha Bam

149. Study of the prevalence of Campylobacter in raw meat and drinking water in water corporation of Kathmandu and possible research for Shigella spp. By: Ita Bhattarai

150. Tubersulosis and human immuno deficiency virus co-infection in united mission hospital, Tansen, Nepal. By: Janak R. Dhungana

151. A prospective study on acute group A streptococcal pharyngitis and its delayed sequelae on school children of Kathmandu Valley, Nepal By: Binod Pd. Pathak

152. Study of the factors associated with enteric parasitic infection among school children in a rural village setting in Kathmandu Valley, Nepal. By: Diyo Ram Rai

153. Anti tuberculosis treatment resistant in pulmonary tuberculosis patients visiting German Nepal tuberculosis project, Kalimati, Kathmandu. By: Narayan Raj Bhattarai

154. Relative study of enteropathogens (parasites and bacteria) in gastroenteritis and its predisposing factors in TUTH. By: Keshav Rai

155. Study of ambient air micro flora of Kathmandu Valley and its relation to particulate matters. By: Rajendra Pd. Subedi

156. Prevalence of enteric parasites in HIV/AIDS patients of Nepal. By: Darshan Sapkota

157. Prevalence of lymphatic filariasis in Dhanusha district of Nepal, By: Nagendra Prasad Yadav

158. Study on the prevalence of multiple drug resistant Sammonella spp in poultry birds. By: Madhusudan Pandey

159. Microbial contamination of the contact lens and its care system in the patients visiting BPK lion center for ophthalmic studies, Maharajgunj, Kathmandu. By: Pallavi Gurung

160. Evaluation of nitrate test in detecting urinary tract infection conducted at TUTH. By: Sushil Chandra Regmi

161. Microbial colonization of maternal genital tract and its relationship to onset of early neonatal sepsis. By: Salina Gaire

162. Studies on the antibacterial activity of actinomycetes isolated from Khumbu region of Nepal. By: Bhagwati Pantdey

163. Carriage pattern of S sureus in healthy school children. By: Sachindra R. Joshi

164. Prevalence of urinary tract infection in diabetic patients. By: Preeti Gautam

165. Comparative study of tuberculosis test Ziehl Neelsen staining and culture in the diagnosis of tuberculosis. By: Pratap Shahi

166. Superficial fungal infection and awareness status among the patients visiting dermatology outpatients department of TUTH. By: Niraja Thapa

167. Modulation of whole blood imme to phenolic glycolipid (PGTD of M. Leprae). By: Suraj Dhungel

168. Comparative evaluation of different staining techniques for the diagnosis of tuberculosis lymphadenitis. By: Smritee Pohharel

169. Evaluation of antimicrobial resistance status in Kirtipur community bacterial isolates. By: Manoj Ghimire

170. Air quality assessment of Kathmandu Valley. By: Pukar Acharya

171. Production and  characterijation of the antimicrobial substances from Bacillus species. By: Dipak Adhikari

172. Characterization of proteases from Bacillus species producing antimicrobial substances. By: Bharak Khatiwada

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Source: Microbiological Abstracts (Revised edition 2004). Published by MISAN, Central Department of microbiology, Tribhuvan University, Kirtipur, Kathmandu, Nepal.

Personal genomes: The case of the missing heritability

When scientists opened up the human genome, they expected to find the genetic components of common traits and diseases. But they were nowhere to be seen. Brendan Maher shines a light on six places where the missing loot could be stashed away.
Brendan Maher
If you want to predict how tall your children might one day be, a good bet would be to look in the mirror, and at your mate. Studies going back almost a century have estimated that height is 80–90% heritable. So if 29 centimetres separate the tallest 5% of a population from the shortest, then genetics would account for as many as 27 of them.
This year, three groups of researchers scoured the genomes of huge populations (the largest study looked at more than 30,000 people) for genetic variants associated with the height differences. More than 40 turned up.
But there was a problem: the variants had tiny effects. Altogether, they accounted for little more than 5% of height's heritability — just 6 centimetres by the calculations above. Even though these genome-wide association studies (GWAS) turned up dozens of variants, they did "very little of the prediction that you would do just by asking people how tall their parents are", says Joel Hirschhorn at the Broad Institute in Cambridge, Massachusetts, who led one of the studies.

Height isn't the only trait in which genes have gone missing, nor is it the most important. Studies looking at similarities between identical and fraternal twins estimate heritability at more than 90% for autism5 and more than 80% for schizophrenia. And genetics makes a major contribution to disorders such as obesity, diabetes and heart disease. GWAS, one of the most celebrated techniques of the past five years, promised to deliver many of the genes involved. And to some extent they have, identifying more than 400 genetic variants that contribute to a variety of traits and common diseases. But even when dozens of genes have been linked to a trait, both the individual and cumulative effects are disappointingly small and nowhere near enough to explain earlier estimates of heritability. "It is the big topic in the genetics of common disease right now," says Francis Collins, former head of the National Human Genome Research Institute (NHGRI) in Bethesda, Maryland. The unexpected results left researchers at a point "where we all had to scratch our heads and say, 'Huh?'", he says.


Although flummoxed by this missing heritability, geneticists remain optimistic that they can find more of it. "These are very early days, and there are things that are doable in the next year or two that may well explain another sizeable chunk of heritability," says Hirschhorn. So where might it be hiding?


Right under everyone's noses
The inability to find some genes could be explained by the limitations of GWAS. These studies have identified numerous one-letter variations in DNA called single nucleotide polymorphisms (SNPs) that co-occur with a disease or other trait in thousands of people. But a given SNP represents a much bigger block of genetic material. So, for example, if two people share one of these variants at a key location, both may be scored as having the same version of any height-related gene in that area, even though one person actually has a relatively rare mutation that has a huge effect on height. The association study might identify a variant responsible for the height difference, says Teri Manolio, director of the Office of Population Genomics at the NHGRI, but averaging across hundreds of people could give the appearance that its effects are pretty wimpy. "It's going to be diluted," she says.
Finding this type of missing heritability is conceptually easy, because it involves closer scrutiny of the genes already in hand. "Just exploring, in a very dense way, genetic variation at the loci that have been discovered is probably going to [explain] another increment of missing heritability," Hirschhorn says. Researchers will need to sequence candidate genes and their surrounding regions in thousands of people if they are to unearth more associations with the disease.
Helen Hobbs and Jonathan Cohen of the University of Texas Southwestern Medical Center in Dallas did this in an attempt to capture all the variation in ANGPTL4, a gene their studies had linked to cholesterol and triglyceride concentrations. They sequenced the gene in around 3,500 individuals from the Dallas Heart Study and found that some previously unknown variants had dramatic effects on the concentration of these lipids in the blood. Mark McCarthy of Britain's Oxford Centre for Diabetes, Endocrinology and Metabolism says that such studies could reveal much of the missing heritability, but not a lot of people have had the enthusiasm to do them. This could change as the cost of sequencing falls.

Out of sight
Other variants, for which GWAS haven't even begun to provide clues, will prove even harder to find. In the past, conventional genetic studies for inherited diseases such as cystic fibrosis identified rare, mutated genes that have a high penetrance, meaning that the gene has an effect in almost everyone who carries it. But it quickly became apparent that high-penetrance variants would not underlie most common diseases because evolution largely keeps them in check.
What powered the push into genome-wide association was a hypothesis that common diseases would be caused by common, low-penetrance variants when enough of them showed up in the same unlucky person. Now that hypothesis is being questioned. "A lot of people are recognizing that screening for common variation has delivered less than we had hoped," says David Goldstein, professor of genetics at Duke University in Durham, North Carolina.
But between those variants that stick out like a sore thumb, and those common enough to be dredged up by the wide net of GWAS, there is a potential middle ground of variants that are moderately penetrant but are rare enough that they are missed by the net. There's also the possibility that there are many more-frequent variants that have such a low penetrance that GWAS can't statistically link them to a disease.
These very-low-penetrance variants pose some problems, says Leonid Kruglyak professor of ecology and evolutionary biology at Princeton University in New Jersey. "You're talking about thousands of variants that you would have to invoke to get near 80% or 90% heritability." Taken to the extreme, practically every gene in the genome could have a variant that affects height, for example. "You don't like to think about models like that," Kruglyak says.
If rare, moderately penetrant or common, weakly penetrant variants are the culprits, then bumping up the number of people in existing association studies could help find previously missed genetic associations. Peter Visscher of the Queensland Institute of Medical Research in Brisbane, Australia, says that a meta-analysis of height studies covering roughly 100,000 people is in the works. Lowering the stringency with which an association is made could drag up more, but confidence in the hits would drop.
At some point it might make sense to stop using SNPs, and start sequencing whole genomes. Collins suggests that the NHGRI's 1,000 genomes project, which aims to sequence the genomes of at least 1,000 people from all over the world, could go a long way towards finding hidden heritability, and many more genomes may become possible as the price of sequencing falls.
Not everyone supports an all-out sequencing onslaught. Goldstein warns against continuing to "turn the crank" without devising a more rational approach, such as sequencing the genomes of people who exhibit extreme manifestations of diseases. "I'm not really sold on doing the sequencing version of what we did with [GWAS]," he says. "It's a big enough, costly enough job, that I think we want to think a little bit harder about exactly who gets re-sequenced."

In the architecture
Some researchers are now homing in on copy-number variations (CNVs), stretches of DNA tens or hundreds of base pairs long that are deleted or duplicated between individuals. Variations in these features could begin to explain missing heritability in disorders such as schizophrenia and autism, for which GWAS have turned up almost nothing. Two recent studies looked at hundreds of CNVs in normal people and in those with schizophrenia, and found strong associations between the disease and several CNVs. They commonly arise de novo — in an individual without any family history of the mutation.
These structural variants might account for a lot of the genetic variability from person to person and could account for some of those rare 'out-of-sight' mutations with moderate penetrance that GWAS can't pick up. Many CNVs go undetected because they don't alter SNP sequences. Duplicated regions can also be difficult to sequence.
A standard technology for uncovering CNVs is array comparative genomic hybridization, in which scientists examine how genetic material from different individuals hybridizes to a microarray. If certain spots on an array pick up more or less DNA, it could indicate that there's a CNV. This and several other techniques are being tested by a consortium called the Copy Number Variation Project, run out of the Wellcome Trust Sanger Institute in Cambridge, UK. The consortium is dedicated to characterizing as many CNVs as possible so that associations can be made between them and diseases. McCarthy says that the role hidden CNVs have in heritability "should play out in the next six months to a year". But Goldstein argues that current technologies will miss many of the smaller CNVs, from 50 base pairs down to repeats of just two bases. "All we'll have verification of is the big whopping CNVs that are identifiable, and they clearly do not account for much of the missing heritability."

In underground networks
Most genes work together with close partners, and it is possible that the effects of one on heritability cannot be found without knowing the effects of the others. This is an example of epistasis, in which one gene masks the effect of another, or where several genes work together. Two genes may each add a centimetre to height on their own, for example, but together they could add five. GWAS don't cope with epistasis very well, and efforts to find these interactions usually require good up-front guesses about the interacting partners.
Joseph Nadeau, a geneticist at Case Western Reserve University in Cleveland, Ohio, says that 'modifier' genes act even in some straightforward single-gene diseases. "That's a simple kind of epistasis," he says. Cystic fibrosis, for example, is usually caused by mutations in one gene, CFTR, yet can vary greatly in symptoms and severity. The suspicion has been that modifier genes are one cause of this variability.
But despite the years of study, researchers still struggle to pin down these genes. "People haven't modelled truly the effect of epistasis," says population geneticist Sarah Tishkoff at the University of Pennsylvania in Philadelphia.
It's no surprise that genetics is more complicated than one gene, one phenotype, or even several genes, one phenotype, but it's humbling to realize how much more complex things are starting to look. In a now classic study, Kruglyak and his colleagues found that expression of most yeast genes is controlled by several variants, often more than five. To fill in all the heritability blanks, researchers may need better and more varied models of the entire network of genes and regulatory sequences, and of how they act together to produce a phenotype. At some point this process starts to look more like systems biology, and researchers are already applying systems methods to humans and other organisms. "What we're learning from these studies is that we need to think about the more complex of the complex models rather than the more simple of the complex models," Kruglyak says.Chronic Schizophrenia and Adult Autism: Issues in Diagnosis, Assessment, and Psychological TreatmentAutism Spectrum Disorders: The Complete Guide to Understanding Autism, Asperger's Syndrome, Pervasive Developmental Disorder, and Other ASDs