Thesis Defense: Dr. Jong Wha (Joanne) Joo

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Jong Wha (Joanne) Joo successfully defended her thesis,”Design of efficient and accurate statistical approaches to correct for confounding effects in genetic association studies,” on Friday, December 4, 2015 in Boelter 4760.  Her talk, which is posted on our YouTube channel ZarlabUCLA, discusses using a mixed model analysis (GAMMA) to efficiently analyzes large numbers of phenotypes while simultaneously considering population structure, an expression quantitative trait loci (eQTL) mapping tool to eliminate spurious hotspots while retaining genuine regulatory hotspots, and a multiple testing correction method (slideLMM) for linear mixed models.
More details about her research are available in the three papers she discusses:

Joo, Jong Wha J; Hormozdiari, Farhad; Han, Buhm; Eskin, Eleazar

Multiple testing correction in linear mixed models. Journal Article

In: Genome Biol, 17 (1), pp. 62, 2016, ISSN: 1474-760X.

Abstract | Links | BibTeX

Joo, Jong Wha J; Kang, Eun Yong; Org, Elin; Furlotte, Nick; Parks, Brian; Lusis, Aldons J; Eskin, Eleazar

Efficient and Accurate Multiple-Phenotypes Regression Method for High Dimensional Data Considering Population Structure Book Chapter

In: Research in Computational Molecular Biology, pp. 136-153, Springer International Publishing, 2015.

Abstract | Links | BibTeX

Joo, Jong Wha J; Sul, Jae Hoon ; Han, Buhm ; Ye, Chun ; Eskin, Eleazar

Effectively identifying regulatory hotspots while capturing expression heterogeneity in gene expression studies. Journal Article

In: Genome Biol, 15 (4), pp. R61, 2014, ISSN: 1465-6914.

Abstract | Links | BibTeX

Genetic and Environmental Control of Host-Gut Microbiota Interactions

Studies carried out over the last decade have revealed that gut microbiota contribute to a variety of common disorders, including obesity and diabetes (Musso et al. 2011), colitis (Devkota et al. 2012), atherosclerosis (Wang et al. 2011), rheumatoid arthritis (Vaahtovuo et al. 2008), and cancer (Yoshimoto et al. 2013). The evidence for metabolic interactions is particularly strong, as a large body of data now supports the conclusion that gut microbiota influence the energy harvest from dietary components, particularly complex carbohydrates, and that metabolites such as the short chain fatty acids produced by gut bacteria can perturb metabolic traits, including adiposity and insulin resistance (Turnbaugh et al. 2006; Backhed et al. 2007; Wen et al. 2008; Turnbaugh et al. 2009; Ridaura et al. 2013).

Gut microbiota communities are assembled by generation, influenced by maternal seeding, environmental factors, host genetics and age, resulting in substantial variations in composition among individuals in human populations (Eckburg et al. 2005; Costello et al. 2009; Huttenhower and Consortium 2012; Goodrich et al. 2014). Most experimental studies of host-gut microbiota interactions have employed large perturbations, such as comparisons of germ-free versus conventional mice, and the significance of common variations in gut microbiota composition for disease susceptibility is still poorly understood. Furthermore, while studies with germ-free mice have clearly implicated microbiota in clinically relevant traits, it has proven difficult to identify the responsible taxa of bacteria.

We now report a population-based analysis of host-gut microbiota interactions in the mouse. One of the issues we explore is the role of host genetics. Although some evidence is consistent with significant heritability of gut microbiota composition, the extent to which the host controls microbiota composition under controlled environmental conditions is unclear. We also examine the role of common variations in gut microbiota in metabolic traits such as obesity and insulin resistance. We performed our study using a resource termed the Hybrid Mouse Diversity Panel (HMDP), consisting of about 100 inbred strains of  mice that have been either sequenced or subjected to high density genotyping (Bennett et al. 2010). The resource has several advantages for genetic analysis as compared to traditional genetic crosses. First, it allows high resolution mapping by association rather than linkage analysis, and it has now been used for the identification of a number of novel genes underlying complex traits (Farber et al. 2011; Lavinsky et al. 2015; Parks et al. 2015; Rau et al. 2015). Second, since the strains are permanent the data from separate studies can be integrated, allowing the development of large, publically available databases of physiological and molecular traits relevant to a variety of clinical disorders (systems.genetics.ucla.edu and phenome.jax.org). Third, the panel is ideal for examining gene-by-environment interactions, since it is possible to examine individuals of a particular genotype under a variety of conditions (Orozco et al. 2012; Parks et al. 2013).

Genetics provides a potentially powerful approach to dissect host-gut microbiota interactions. Using a SNP-based approach with a linear mixed model we estimated the heritability of microbiota composition. We conclude that in a controlled environment the genetic background accounts for a significant fraction of abundance of most common microbiota.The mice were previously studied for response to a high fat, high sucrose diet, and we hypothesized that the dietary response was determined in part by gut microbiota composition. We tested this using a cross-fostering strategy in which a strain showing a modest response, SWR, was seeded with microbiota from a strain showing a strong response, AxB19. Consistent with a role of microbiota in dietary response, the cross-fostered SWR pups exhibited a significantly increased response in weight gain. To examine specific microbiota contributing to the response, we identified various genera whose abundance correlated with dietary response. In an effort to further understand host-microbiota interactions, we mapped loci controlling microbiota composition and prioritized candidate genes. Our publically available data provide a resource for future studies.

In our study, we concluded:

– In a total of 599 mice, 75% of them abundantly exhibited the same 17 genera

– These 17 genera accounted for 68% of reads

– Consistent with previous studies, changing diet drastically changes gut microbiota composition, and these shifts are strongly dependent on the genetic background of the mice

– Gut microbiota contribute to dietary responsiveness

– Several gut microbiota (known and novel to this study) contribute to obesity and metabolic phenotypes

– seven genome-wide significant loci (P < 4 x 10-6) were found to be associated with common genera

– We were able to estimated the heritability by using a linear mixed model approach andassuming an additive effect based on the proportion of phenotype variance accounted for by genetic relationships among the strains.

We began our study with the hypothesis that the dietary response was dictated in part by differences in gut microbiota. We showed that different inbred strains of mice differ strikingly in the composition of gut microbiota and provided evidence that the variation is determined in part by the host genetic background. Consistent with our hypothesis, we showed that cross-fostering between two strains of mice affected dietary response to the high fat, high sucrose diet. By correlating microbiota composition with dietary response among the HMDP inbred strains, we were able to identify several candidate microbiota influencing dietary response.

For all the details of our research and our methods, read our paper:

Org, Elin; Parks, Brian W W; Joo, Jong Wha J; Emert, Benjamin; Schwartzman, William; Kang, Eun Yong; Mehrabian, Margarete; Pan, Calvin; Knight, Rob; Gunsalus, Robert; Drake, Thomas A; Eskin, Eleazar; Lusis, Aldons J

Genetic and environmental control of host-gut microbiota interactions. Journal Article

In: Genome Res, 2015, ISSN: 1549-5469.

Abstract | Links | BibTeX

Identifying genetic relatives without compromising privacy

Our DNA can tell us a lot about who our relatives are. Recently, several companies including 23andMe and AncestryDNA now provide services where they collect DNA from individuals and then match the DNA to a database of the DNA of other people to identify relatives. Relatives are then informed by the company that their DNAs match. Our lab was interested if we can perform this same type of service but without involving a company and more generally without involving any third party. One way to do this would be to have individuals obtain their own DNA sequences and then share their DNA sequences directly with each other. Unfortunately, DNA sequences are considered medical information and it is inappropriate to share them in this way.

Through a collaboration between our lab and the UCLA cryptography group, we recently published a paper that combines cryptography and genetics which describes an approach for identifying relatives without compromising privacy. Our paper was published in the April 2014 issue of Genome Research. The key ideas is that individuals release an encrypted version of their DNA information. Another individual can download this encrypted version and then use their own DNA information to try to decrypt it. If the are related to each other, their DNA sequences will be close enough that the decryption will work telling the individual that they are related. While if they are unrelated, the decryption will fail. What is important in this approach is that individuals who are not related do not obtain any information about each other’s DNA sequences.

The intuitive idea behind the approach is the following. Individuals each release a copy of their own genomes encrypted with a key that is based on the genome itself. Other users then download this encrypted information and try to decrypt it using their own genomes as the key. The encryption scheme is designed to allow for decryption if the encrypting key and decrypting key are “close enough”. Since related individuals share a portion of their genomes, we set the threshold for “close enough” to be exactly the threshold of relatedness that we want to detect.

Our approach uses a relatively new type of cryptographic technique called Fuzzy Extractors which were pioneered by our co-authors on this study, Amit Sahai and Rafail Ostrovsky. This type of technique allows for encryption and decryption with keys that match inexactly. Students in our group who were involved are Dan He, Nick Furlotte, Farhad Hormozdiari, and Jong Wha (Joanne) Joo. This research was supported by National Science Foundation grant 1065276.

The full citation of our paper is here:

He, Dan; Furlotte, Nicholas A; Hormozdiari, Farhad ; Joo, Jong Wha J; Wadia, Akshay ; Ostrovsky, Rafail ; Sahai, Amit ; Eskin, Eleazar

Identifying genetic relatives without compromising privacy. Journal Article

In: Genome Res, 2014, ISSN: 1549-5469.

Abstract | Links | BibTeX